Dendritic cells : tools to induce efficient T cell mediated immunity Schuurhuis, D.H.
39
0
0
Hele tekst
(2) #HAPTER . =[d[hWb?djheZkYj_ed.
(3)
(4) 'ENERAL INTRODUCTION. 'ENERAL )NTRODUCTION 4HE IMMUNE SYSTEM PROVIDES SEVERAL MECHANISMS TO PROTECT US AGAINST A LARGE VARIETY OF INFECTIOUS MICROBIAL AGENTS
(5) LIKE VIRUSES
(6) BACTERIA
(7) FUNGI AND PARASITES 4HE NON SPECIl C
(8) INNATE IMMUNE SYSTEM
(9) INCLUDING PHYSICAL BARRIERS AND COMPLEMENT MEDIATED IMMUNITY
(10) FUNCTIONS AS A l RST LINE OF DEFENSE AGAINST INVADING MICRO ORGANISMS 4HE INNATE IMMUNE SYSTEM DOES NOT DISCRIMINATE BETWEEN THE DIFFERENT MICROBES
(11) BUT RECOGNIZES COMMON STRUCTURES SHARED BETWEEN PATHOGENS 4HE ADAPTIVE IMMUNE SYSTEM ON THE OTHER HAND HAS TWO UNIQUE FEATURES )T DISTINGUISHES DISTINCT MICRO ORGANISMS AND CONFERS IMMUNOLOGICAL MEMORY
(12) SO THAT THE RESPONSE UPON SUBSEQUENT ENCOUNTERS WITH A PATHOGEN IS INCREASINGLY EFl CIENT 4HE SPECIl CITY IS MEDIATED BY MEMBRANE RECEPTORS THAT HAVE A VERY LARGE VARIETY OF STRUCTURES OF ANTIGEN !G BINDING SITES " LYMPHOCYTES USE MEMBRANE IMMUNOGLOBULINS TO BIND SOLUBLE PROTEIN !G
(13) WHICH INDUCES THEIR PROLIFERATION AND DIFFERENTIATION TO IMMUNOGLOBULIN ANTIBODY
(14) !B PRODUCING PLASMA CELLS 4 LYMPHOCYTES
(15) ON THE OTHER HAND
(16) ONLY RECOGNIZE SMALL FRAGMENTS PEPTIDES OF PROTEIN
(17) THAT NEED TO BE BOUND TO MOLECULES OF THE MAJOR HISTOCOMPATIBILITY COMPLEX -(# ON AN !G PRESENTING CELL !0# 5PON RECOGNITION OF THE PEPTIDE -(# COMPLEX BY THE 4 CELL RECEPTOR 4#2
(18) 4 CELLS START TO PROLIFERATE AND EITHER DIFFERENTIATE INTO EFFECTOR CELLS OR ARE TOLERIZED
(19) DEPENDING ON THE OTHER SIGNALS GIVEN BY THE !0# 4WO DIFFERENT CLASSES OF -(# MOLECULES HAVE EVOLVED TO DEAL WITH PROTEIN !G DERIVED FROM EITHER INTRACELLULAR -(# CLASS ) OR EXTRACELLULAR -(# CLASS )) SOURCES 4WO TYPES . OF 4 LYMPHOCYTES CAN BE DISTINGUISHED #$ 4 HELPER 4H CELLS RECOGNIZE PEPTIDE BOUND IN . -(# CLASS ))
(20) WHEREAS #$ CYTOTOXIC 4 LYMPHOCYTES #4, RECOGNIZE PEPTIDE PEPTIDE BOUND IN -(# CLASS ) !MONG !0# DENDRITIC CELLS $# ARE THE MOST EFl CIENT AT INITIATING !G SPECIl C . IMMUNE RESPONSES AND $# CAN INDUCE DIFFERENTIATION OF BOTH NAÕVE #$ AND #$ 4 CELLS $# ARE THE CENTRAL PLAYERS IN THE IMMUNE SYSTEM $# RECEIVE SIGNALS FROM THE INNATE IMMUNE SYSTEM VIA SURFACE RECEPTORS THAT RECOGNIZE PATHOGEN DERIVED LIGANDS )N TURN
(21) $# REGULATE THE ADAPTIVE . IMMUNE SYSTEM BY DELIVERING POSITIVE OR NEGATIVE SIGNALS TO 4 LYMPHOCYTES #$ 4H CELLS
(22) WHICH PLAY AN IMPORTANT ROLE IN INITIATION AND REGULATION OF THE ADAPTIVE IMMUNE RESPONSE
(23) PROVIDE HELP TO #$ #4, AND " LYMPHOCYTES !FTER DIFFERENTIATION TO EFFECTOR CELLS
(24) #4, MEDIATE ERADICATION OF TARGET CELLS WHEREAS " LYMPHOCYTES PRODUCE !B !FTER ACTIVATION BY $#
(25) 4H CELLS SIGNAL BACK TO $# BY UPREGULATING EXPRESSION OF A LIGAND #$, FOR A RECEPTOR #$ THAT IS EXPRESSED ON $# " LYMPHOCYTES SIGNAL BACK TO $# BY PRODUCING !B
(26) WHICH AFTER BINDING TO THEIR !G CAN SIGNAL VIA SPECIl C RECEPTORS &C2 ON $# 4HESE 4H CELL OR " CELL DEPENDENT SIGNALS CAN INDUCE MATURATION OF $# -ATURATION OF $# IS REQUIRED FOR EFl CIENT INDUCTION OF 4 CELL RESPONSES &IGURE SCHEMATICALLY SHOWS THE CENTRAL REGULATORY ROLE OF $# IN THE IMMUNE SYSTEM. $ENDRITIC CELLS AND THE IMMUNE SYSTEM $# ARE PROFESSIONAL !0# WHICH ARE STRATEGICALLY POSITIONED AT THE BOUNDARIES BETWEEN THE INNER AND THE OUTSIDE WORLD
(27) IN THIS WAY BRIDGING INNATE AND ADAPTIVE IMMUNITY ;= 4RANSLOCATING !G FROM THE PERIPHERY TO THE LYMPHOID NICHES IS A PIVOTAL FUNCTION WHEREBY $# INITIATE 4 CELL RESPONSES AGAINST MICROBIAL PATHOGENS AND TUMORS DUE TO THEIR CAPACITY TO STIMULATE NAÕVE 4 CELLS ;= 4HE DEVELOPMENT OF $# IS CONSIDERED TO OCCUR IN DISTINCT STAGES (EMATOPOIETIC PLURIPOTENTIAL STEM CELLS UNDER AS YET UNKNOWN INm UENCES CONSTANTLY GENERATE $# PROGENITORS IN THE BONE MARROW
(28) WHICH GIVE RISE TO CIRCULATING PRECURSORS IN THE BLOOD ;= 4HESE $# PRECURSORS HOME TO A LARGE VARIETY OF TISSUES WHERE THEY RESIDE AS SENTINEL IMMATURE CELLS WITH HIGH ENDOCYTIC AND PHAGOCYTIC CAPACITY ;= )MMATURE $# CAPTURE !G AND
(29) FOLLOWING PROINm AMMATORY SIGNALS THAT ARE OFTEN TRIGGERED BY INFECTIOUS AGENTS
(30) MIGRATE TO THE LYMPHOID ORGANS WHERE
(31) AFTER MATURATION
(32) . THEY PRESENT CAPTURED !G TO NAÕVE 4 CELLS ;=
(33) THEREBY INDUCING DIFFERENTIATION OF NAIVE #$ AND #$ 4 CELLS INTO 4H CELLS AND #4,
(34) RESPECTIVELY !G SPECIl C 4 CELL ACTIVATION REQUIRES THE ENGAGEMENT OF THE 4#2#$ COMPLEX WITH THE ANTIGENIC PEPTIDE PRESENTED BY THE -(# . .
(35) #HAPTER . &IGURE $# PLAY A CENTRAL REGULATORY ROLE IN THE IMMUNE RESPONSE $# RECEIVE SIGNALS FROM THE INNATE IMMUNE SYSTEM VIA SURFACE RECEPTORS 4OLL LIKE RECEPTORS
(36) 4,2 THAT RECOGNIZE PATHOGEN DERIVED LIGANDS )N ADDITION
(37) $# RECEIVE SIGNALS FROM NATURAL KILLER .+ CELLS )N TURN
(38) $# REGULATE THE ADAPTIVE IMMUNE SYSTEM BY DELIVERING POSITIVE OR NEGATIVE SIGNALS TO 4 CELLS #$ 4H CELLS
(39) PROVIDE HELP TO #$ KILLER 4 CELLS #4, AND " LYMPHOCYTES !FTER DIFFERENTIATION TO EFFECTOR CELLS
(40) #4, MEDIATE ERADICATION OF TARGET CELLS
(41) WHEREAS " LYMPHOCYTES PRODUCE !B !FTER ACTIVATION
(42) .+ CELLS KILL THEIR TARGET CELLS 4H CELLS SIGNAL BACK TO $# VIA UPREGULATION OF #$,
(43) WHICH CAN BIND TO #$ ON THE $#
(44) THEREBY INDUCING MATURATION OF THE $# " LYMPHOCYTES SIGNAL BACK TO $# VIA THE PRODUCTION OF !B
(45) WHICH
(46) AFTER BINDING THEIR !G
(47) CAN BIND TO RECEPTORS FOR THE &C DOMAIN OF )G &C2
(48) THEREBY INDUCING MATURATION OF THE $# 4HUS
(49) THE INTERACTION OF $# WITH THE INNATE AND ADAPTIVE IMMUNE SYSTEM IS A DIALOGUE RATHER THAN A MONOLOGUE
(50) DEPENDING ON RECIPROCAL INTERACTIONS. MOLECULES SIGNAL
(51) AS WELL AS THE ENGAGEMENT OF APPROPRIATE CO STIMULATORY RECEPTORS SIGNAL BY CO STIMULATORY LIGANDS ON THE !0# 4HE 4#2 RECOGNIZES AN ANTIGENIC PEPTIDE BOUND TO . -(# CLASS ) #$ 4 CELL OR -(# CLASS )) #$ 4 CELL #$ AND #$ MOLECULES APPEAR TO BE INVOLVED IN THE INTERACTION AS CO RECEPTORS
(52) BINDING TO THE NON POLYMORPHIC SITES ON -(# CLASS . ) OR -(# CLASS ))
(53) RESPECTIVELY #$ #4, ARE CAPABLE OF LYSING CELLS BEARING FOREIGN EPITOPES #$ CELLS HAVE A TWO FOLD FUNCTION 4HEY PROVIDE HELP IN THE FORM OF CYTOKINES TO " CELLS AND OTHER 4 CELLS IN ORDER TO BECOME ACTIVATED
(54) MEDIATED BY 4H TYPE 4H AND 4H TYPE 4H . CELLS
(55) RESPECTIVELY #$ 4H CELLS ALSO REGULATE OTHER IMMUNE EFFECTORS
(56) SUCH AS " CELLS
(57) AS WELL AS . NON !G SPECIl C MACROPHAGES
(58) EOSINOPHILS
(59) AND NATURAL KILLER .+ CELLS ;= #$ 4 CELLS ATTACK -(# CLASS )) POSITIVE CELLS PRESENTING FOREIGN !G BY EITHER ACTIVATION OF NON SPECIl C CELLS SUCH AS MACROPHAGES AND GRANULOCYTES OR BY DIRECT CYTOTOXICITY !N IMPORTANT COGNATE EVENT IN THE DEVELOPMENT OF CELL MEDIATED IMMUNITY IS THE INTERACTION BETWEEN #$ AND #$ LIGAND #$, #$ IS FAIRLY WIDELY DISTRIBUTED AND IS EXPRESSED ON " LYMPHOCYTES
(60) MONOCYTES AND $#
(61) BUT ALSO ON ENDOTHELIAL AND EPITHELIAL CELLS ;= 4HE LIGAND OF #$ #$, OR #$ HAS A MORE RESTRICTED DISTRIBUTION
(62) BEING MAINLY EXPRESSED BY ACTIVATED #$ 4 LYMPHOCYTES ;= ,IGATION OF #$ ON $# RESULTS IN MATURATION OF THE $# ;=
(63) WHICH IS CRUCIAL FOR THE PRIMING OF EFl CIENT 4 CELL RESPONSES ;= )N THE hLICENCE TO KILLv MODEL ; = 4H CELLS INDUCE MATURATION OF !0#
(64) THEREBY LICENCING THEM TO DIRECTLY ACTIVATE #4, )N ADDITION TO 4H CELLS
(65) INm AMMATORY CYTOKINES TUMOR NECROSIS FACTOR 4.& _ OR INTERLEUKIN ),
(66) BACTERIAL COMPONENTS SUCH AS LIPOPOLYSACCHARIDE ,03 OR !G !B IMMUNE COMPLEXES )# CAN INDUCE MATURATION OF $# -ATURATION OF $# IS CHARACTERIZED BY A DECREASED !G PROCESSING CAPACITY AND AN INCREASED CELL SURFACE EXPRESSION OF -(# AND CO STIMULATORY MOLECULES ;= )N ADDITION
(67) REARRANGEMENT OF CYTOSKELETON ;=
(68) ADHESION MOLECULES ;=
(69) AND CYTOKINE RECEPTORS ;= UPON MATURATION ALLOWS $# TO MIGRATE FROM PERIPHERAL TISSUES TO SECONDARY LYMPHOID ORGANS
(70) WHERE 4 CELL PRIMING OCCURS !LTHOUGH IT IS KNOWN THAT $# ARE CRITICAL IN INITIATING 4 CELL IMMUNITY
(71) EMERGING EVIDENCE SUGGESTS THAT $# ALSO PLAY A ROLE IN THE REGULATION OF SUCH RESPONSES &OR EXAMPLE
(72) DISTINCT $# SUBSETS CAN DIFFERENTIALLY REGULATE THE 4H4H BALANCE IN VIVO ; = AND IN VITRO ;= .OT ONLY SHOULD THE IMMUNE SYSTEM ATTACK THAT WHICH IS FOREIGN OR ABERRANT
(73) IT SHOULD ALSO LEAVE ALONE THAT WHICH IS NEITHER TO AVOID AUTOIMMUNITY ;= 4HUS
(74) $# CONSTITUTE A COMPLEX SYSTEM OF CELLS THAT
(75) UNDER DIFFERENT MICROENVIRONMENTAL CONDITIONS
(76) CAN INDUCE SUCH CONTRASTING STATES AS IMMUNITY AND TOLERANCE ;= !CCORDING TO "ANCHEREAU AND 3TEINMAN ;= IT IS CLEAR THAT THERE ARE SOME RAISONS DÐTRE RAISONS DÐTRE FOR A SPECIALIZED $# SYSTEM 4HE INITIATION OF 4 CELL IMMUNITY IS RATHER DEMANDING )NITIALLY
(77) PEPTIDES . .
(78) 'ENERAL INTRODUCTION. 4ABLE ) %XPRESSION OF SURFACE MARKERS ON HUMAN AND MOUSE $# SUBSETS %XPRESSION LEVELS ARE INDICATED ABSENT LOW ¢ INTERMEDIATE HIGH 7HEN NOTHING IS MENTIONED IN THE TABLE
(79) NO INFORMATION ABOUT EXPRESSION OF THE INDICATED MARKER ON THAT $# SUBSET WAS FOUND IN LITERATURE 4ABLE ) - $#. 0 $#. , $#. 3URFACE !G. HUMAN. MOUSE. HUMAN. MOUSE. MOUSE. #$ #$A #$C #$ #$ #$ #$ #$ #$ #$ #$ #$2/ #$2! #$ #$. . OR n . . . . . ¢ ¢. . ##2 #8#2 ),4 ),4. . . -(# CLASS )). . . . ¢. . . . . . . . . . . . EXPRESSION ON MYELOID $# - $#. EXPRESSION ON PLASMACYTOID $# 0 $#. EXPRESSION ON LYMPHOID $# , $#. FROM INFECTED CELLS LOCATED ANYWHERE IN THE BODY MUST BE FOUND AND RECOGNIZED BY 4 CELLS THAT CIRCULATE IN THE BLOOD STREAM 4HE AMOUNTS OF SPECIl C !G -(# COMPLEXES ON TUMORS AND INFECTED CELLS ARE TYPICALLY SMALL
(80) AND MUST BE RECOGNIZED BY RARE 4 CELL CLONES THROUGH A 4#2 THAT HAS A LOW AFl NITY -OREOVER
(81) INFECTED CELLS AND TUMORS FREQUENTLY LACK THE CO STIMULATORY MOLECULES THAT DRIVE CLONAL EXPANSION OF THE 4 CELL
(82) THE PRODUCTION OF CYTOKINES
(83) AND DEVELOPMENT INTO KILLER CELLS 4HE $# SYSTEM PROVIDES A POWERFUL WIDELY DISTRIBUTED CELLULAR SENTINEL APPARATUS TO SOLVE THESE CHALLENGES . $ENDRITIC CELL SUBSETS )N THE PAST
(84) IT HAS BECOME GENERALLY ACCEPTED THAT $# ARE A DISTINCT LINEAGE OF !0# WITH POTENT CAPACITY TO INDUCE PRIMARY 4 CELL MEDIATED IMMUNE RESPONSES (OWEVER
(85) ACCUMULATING EVIDENCE HAS DEMONSTRATED THAT THE $# SYSTEM BEARS MUCH MORE PLASTICITY THAN ORIGINALLY THOUGHT $# SHOULD BE LOOKED AT AS A MULTILINEAGE SYSTEM OF LEUKOCYTES WITH VARIABLE FUNCTIONS RATHER THAN A HOMOGENOUS CELL TYPE WITH PREDETERMINED FUNCTIONAL PROPERTIES (UMAN $# SUBSETS. 4WO SUBSETS OF $# WERE IDENTIl ED IN THE HUMAN BLOOD BASED ON THE EXPRESSION OF THE ` INTEGRIN
(86) . .
(87) #HAPTER . #$C ;= %ACH OF THE SUBSETS REPRESENT A SMALL FRACTION ^ OF THE ENTIRE CIRCULATING BLOOD LEUKOCYTE POPULATION ;= -ORE RECENT WORK HAS CHARACTERIZED THESE TWO SUBSETS AS BELONGING TO THE MYELOID OR LYMPHOID LINEAGE AND
(88) ALTHOUGH DIFFERENT DENOMINATIONS HAVE BEEN USED
(89) THEY CAN BE DEl NED AS MYELOID $# - $# AND PLASMACYTOID $# 0 $# ; = - $# AND 0 $# DIFFER IN MORPHOLOGY
(90) EXPRESSION OF MARKERS AND FUNCTION "OTH $# SUBSETS - $# AND 0 $# ALSO SHARE MARKERS
(91) SUCH AS ADHESION MOLECULES
(92) CO STIMULATORY MOLECULES
(93) ACTIVATION MARKERS AND INHIBITORY MOLECULES 4ABLE ) SHOWS SURFACE MARKER PROl LES OF THESE $# SUBSETS - $# ARE CHARACTERIZED BY A MONOCYTIC MORPHOLOGY
(94) POSSESSING AN IRREGULAR OUTLINE AND A HYPERLOBULATED NUCLEUS - $# EXPRESS MYELOID MARKERS LIKE #$
(95) #$
(96) THE ` INTEGRIN #$C AND LOW LEVELS OF THE ), 2 _ CHAIN #$ ; = - $# ARE ABLE TO PRESENT LIPID !G TO 4 CELLS THROUGH EXPRESSION OF -(# CLASS ) LIKE MOLECULES SUCH AS #$A
(97) B
(98) C AND D ;= )N CONTRAST TO 0 $# PRECURSORS
(99) - $# PRECURSORS EXPRESS HIGH LEVELS OF THE MANNOSE RECEPTOR AND CAN RAPIDLY TAKE UP LARGE AMOUNTS OF POLYSACCHARIDE !G ;= 0ERIPHERAL BLOOD MONOCYTES GIVE RISE TO IMMATURE - $# AFTER CULTURING WITH GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR '- #3& AND ), ;= &UNCTIONALLY
(100) - $# CAPTURE !G IN THE PERIPHERAL TISSUES BY BOTH PHAGOCYTOSIS AND MACROPINOCYTOSIS ;= !FTER !G UPTAKE
(101) THESE IMMATURE - $# MIGRATE TO LYMPH NODES 3TIMULATION WITH #$, OR ENDOTOXIN ;= INDUCES THE MATURATION OF - $# "ASED ON THEIR ABILITY TO PRODUCE ), IN RESPONSE TO ,03 AND PROSTAGLANDIN 0' OR #$, STIMULATION ;=
(102) - $# WERE REGARDED AS A 4H DRIVING !0# TYPE THAT INDUCED THE . DIFFERENTIATION OF NAÕVE #$ 4 CELLS INTO #4, ;=
(103) AND THEREFORE DESIGNATED AS $# ;= (OWEVER
(104) SEVERAL IN VITRO AND IN VIVO STUDIES SHOW THAT - $# ARE POTENT INDUCERS OF BOTH 4H AND 4H CYTOKINES IN NAÕVE 4H CELLS ; = !N ESSENTIAL DISCRIMINATIVE FACTOR APPEARS NOT TO BE THE ABILITY TO PRODUCE ), PER SE
(105) BUT RATHER THE LEVEL OF ), PRODUCED ;= 4HUS
(106) BY INDUCING ), PRODUCTION IN $#
(107) BACTERIA
(108) BACTERIAL COMPOUNDS
(109) OR EXOGENOUS INTERFERON )&. a
(110) EG DERIVED FROM ACTIVATED BYSTANDER MEMORY 4 CELLS OR .+ CELLS
(111) WILL PROMOTE THE DEVELOPMENT OF 4H RESPONSES ;= #ONVERSELY
(112) 4H RESPONSES WILL BE FACILITATED BY MICROENVIRONMENTAL FACTORS THAT INHIBIT THE PRODUCTION OF ), BY $#
(113) SUCH AS ), ;= AND 0'% ;= .EITHER A 4H NOR A 4H INDUCING FUNCTION IS AN INTRINSIC ATTRIBUTE OF HUMAN - $#
(114) BUT APPEARS TO DEPEND ON ENVIRONMENTAL INSTRUCTION ;= 0 $#
(115) DERIVED FROM A LYMPHOID LINEAGE ;=
(116) HAVE A MORPHOLOGY RESEMBLING PLASMA CELLS POSSESSING A ROUNDED MORPHOLOGY WITH AN OVAL OR INDENTED NUCLEUS AND A PROMINENT PERINUCLEAR PALE ZONE 0 $# ARE DEVOID OF MYELOID MARKERS SUCH AS #$ AND #$ AND EXPRESS HIGH LEVELS OF #$ THE _ CHAIN OF THE ), 2
(117) #8# CHEMOKINE RECEPTOR #8#2
(118) AND -(# CLASS )) MOLECULES ;= )N CONTRAST TO - $#
(119) 0 $# DO NOT EXPRESS #$C ;= )N ADDITION
(120) 0 $# SPECIl CALLY EXPRESS A UNIQUE LECTIN RECOGNIZED BY THE MONOCLONAL !B "$#! !G BINDING TO THIS LECTIN IS EFl CIENTLY TAKEN UP
(121) PROCESSED AND PRESENTED TO 4 CELLS ;= 0 $# FROM BLOOD OR TONSILS GIVE RISE TO A DISTINCT TYPE OF IMMATURE $# AFTER CULTURE WITH ), ;= 4HESE CELLS DIFFERENTIATE INTO MATURE $# AFTER #$, STIMULATION ;= AND INDUCE 4 CELL RESPONSES WITH A 4H PHENOTYPE ;= )N COMPARISON TO - $#
(122) 0 $# PRODUCE VERY LOW AMOUNTS OF ),
(123) UPON #$, STIMULATION ;= 7ITHOUT ), IN THE MEDIUM THEY DIE RAPIDLY BY APOPTOSIS #$, TOGETHER WITH ), PROMOTES THE DIFFERENTIATION OF 0 $# INTO $# THAT EXPRESS LITTLE #$
(124) #$ AND #$A ;= 0 $# WERE DESIGNATED AS $# ;= FOR THEIR ABILITY TO INDUCE 4H TYPE RESPONSES ;= 2ECENTLY
(125) HOWEVER
(126) IT WAS DISCOVERED THAT UPON EXPOSURE TO VIRUSES
(127) 0 $# PRODUCE VERY HIGH LEVELS OF )&. _
(128) A TYPE ) INTERFERON ;= )N HUMAN BEINGS TYPE ) )&.S ARE 4H POLARIZING CYTOKINES AND INDEED
(129) AFTER EXPOSURE TO VIRUSES
(130) 0 $# HAVE BEEN SHOWN TO INDUCE POTENT 4H RESPONSES ;= -OREOVER
(131) IT HAS BEEN SHOWN THAT 0 $# INDUCE ), PRODUCING #$ 4 CELLS ;= 4HUS
(132) 0 $# ARE SHOWN TO BE ABLE TO INDUCE BOTH 4H AND 4H RESPONSES UNDER DIFFERENT CONDITIONS ;= 4HE COMBINATION OF THE ABILITIES TO PICK UP !G
(133) CARRY IT FROM PERIPHERAL TISSUES TO THE DRAINING LYMPH NODES
(134) AND STIMULATE NAÕVE 4H CELLS EFl CIENTLY IS A UNIQUE PROPERTY OF - $# . .
(135) 'ENERAL INTRODUCTION. ;= )N CONTRAST
(136) 0 $# ARE INEFl CIENT IN !G CAPTURE BY PHAGOCYTOSIS AND MACROPINOCYTOSIS AT ALL MATURATION STAGES ;= - $# ARE LOCATED AT SITES OF PATHOGEN ENTRY SUCH AS SKIN AND MUCOSAL TISSUES 0 $# ON THE OTHER HAND ARE MAINLY LOCATED WITHIN THE 4 CELL AREAS OF LYMPHOID TISSUES UNDER NORMAL PHYSIOLOGICAL CONDITIONS ;= AND THEREFORE MAY BE SPECIALIZED TO RECOGNIZE SELF !G OR BLOOD BORNE PATHOGENS SUCH AS VIRUSES;= -URINE $# SUBSETS. )N MICE SPLENIC $# WERE ORIGINALLY SEPARATED INTO #$ _ #DB AND #$_ #$B SUB POPULATIONS
(137) EACH EXPRESSING #$C ;= #$ EXPRESSION ON $# IS IN THE FORM OF AN __. HOMODIMER RATHER THAN THE _` HETERODIMER THAT IS TYPICAL OF 4 CELLS !LL #$ MOUSE $# WERE . THOUGHT TO DERIVE FROM LYMPHOID RESTRICTED PRECURSORS
(138) AND ALL #$ $# TO DERIVE FROM MYELOID PRECURSORS
(139) LEADING TO THE TERMS |LYMPHOID| AND |MYELOID| $# , $# AND - $# (OWEVER
(140) THIS CONCEPT HAS PROVEN NOT TO BE CORRECT 4HE ISOLATION OF LYMPHOID AND MYELOID PRECURSOR CELLS FROM BONE MARROW SHOWED THAT BOTH PRECURSORS COULD PRODUCE ALL THE MATURE SPLENIC AND THYMIC $# TYPES ; = 3TUDIES OF THE KINETICS OF $# SUBSET LABELLING AFTER CONTINUOUS ADMINISTRATION OF A $.! PRECURSOR TO MICE HAVE INDICATED THAT $# SUBTYPES ARE NOT PRODUCTS OF EACH OTHER AND THAT ALL SUBTYPES ARE SHORT LIVED ;= ! DEGREE OF $# SUBLINEAGE COMMITMENT MUST THEREFORE OCCUR DOWNSTREAM OF THE EARLY HEMOPOIETIC PRECURSORS 'ENETIC EVIDENCE FOR SEPARATE PATHWAYS OF $# DEVELOPMENT COMES FROM THE STUDY OF MICE THAT ARE DEl CIENT IN CERTAIN GENES 4HUS 2EL" MICE ARE DEl CIENT IN #$ _ $#
(141) MICE BEARING A MUTANT )KAROS GENE ARE DEl CIENT IN #$ _ $# ;= 3URFACE MARKER PROl LES OF $# SUBSETS ARE SHOWN IN 4ABLE ) )N CONTRAST TO #$_ $#
(142) #$_ $# EXPRESS #$D AND LECTIN $%# #$ _ $# ARE CONCENTRATED IN THE 4 CELL AREAS IN THE SPLEEN #$ _ $# HAVE THE ABILITY TO PRODUCE LARGE AMOUNTS . OF ),
(143) INDUCE 4H RESPONSES ;=
(144) AND CROSS PRIME #$ 4 CELLS ; = #$ _ $# ARE CONCENTRATED IN THE MARGINAL ZONES OF THE SPLEEN
(145) BUT MIGRATE INTO THE 4 CELL ZONES ON STIMULATION WITH MICROBIAL PRODUCTS ;= #$ _ $# DO NOT HAVE THE ABILITY TO PRODUCE LARGE AMOUNTS OF . ), 4HEY PREFERENTIALLY INDUCE 4H RESPONSES AND DO NOT HAVE THE ABILITY TO CROSS PRIME #$. 4 CELLS ;= 2ECENTLY
(146) THE #$ _ #$B $# SUBSET WAS FURTHER SUBDIVIDED INTO A #$ SUBSET AND A #$ SUBSET ;= 4HE FUNCTIONAL DIFFERENCES BETWEEN THESE TWO SUBSETS ARE CURRENTLY UNKNOWN -ORE RECENTLY A THIRD SUBSET OF MURINE $# HAS BEEN IDENTIl ED
(147) THE MURINE 0 $# 0 $# EXPRESS ,Y# AND " AND HAVE LOW LEVELS OF #$C 4HE MOUSE HOMOLOG OF 0 $# WAS PURIl ED DIRECTLY FROM LYMPHOID ORGANS ; = -OUSE 0 $# SHARE WITH HUMAN 0 $# THE CHARACTERISTIC PLASMACYTOID APPEARANCE
(148) THE HIGH )&._ PRODUCTION IN RESPONSE TO VIRAL AND OTHER MICROBIAL STIMULI AS WELL AS THE EXPRESSION OF MANY SURFACE MARKERS (OWEVER
(149) THEY LACK #$ EXPRESSION AND EXPRESS "
(150) #$C AND 'R )N MICE THE FUNCTIONAL PLASTICITY OF $# IS MOSTLY DEPENDENT ON THE TYPE OF PATHOGEN AND ON THE TISSUE MICROENVIRONMENT 4HE FUNGUS #ANDIDA ALBICANS FOR EXAMPLE STIMULATES $# TO PRO DUCE ), AND INDUCE 4H RESPONSES AT THE YEAST STAGE !T THE HYPHAE STAGE
(151) HOWEVER
(152) # ALBICANS STIMULATES $# TO PRODUCE ), AND INDUCE 4H RESPONSES ;= &URTHERMORE
(153) $# ISOLATED FROM 0EYER|S PATCHES ;=
(154) RESPIRATORY TRACT ;= AND LIVER ;= PREFERENTIALLY INDUCE 4H DIFFERENTIATION )N CONTRAST
(155) $# FROM THE SPLEEN PREFERENTIALLY INDUCE 4H DIFFERENTIATION 2ECENTLY IT HAS BEEN SHOWN THAT
(156) IN ADDITION TO 0 $#
(157) - $# ALSO PRODUCE )&. _ UPON INFECTION WITH VIRUSES ;= 4HESE DIFFERENCES MAY REm ECT DIFFERENCES IN THE TISSUE CYTOKINE MICROENVIRONMENT AND EXPOSURE TO PARTICULAR PATHOGENS
(158) AS WELL AS DIFFERENCES IN THE LINEAGE ORIGIN OF DIFFERENT TISSUE $# 3INCE $# PRODUCE PRO INm AMMATORY CYTOKINES
(159) CHEMOKINES AND ), ONLY FOR BRIEF PERIODS OF TIME
(160) . .
(161) #HAPTER . AND AT DEl NED STAGES OF MATURATION
(162) THIS MIGHT ALSO INm UENCE THE OUTCOME OF THE RESPONSE ;=. !NTIGEN PROCESSING 0RESENTATION OF ENDOCYTOSED ANTIGENS IN -(# CLASS )). 4O SAMPLE THEIR ENVIRONMENT IN PERIPHERAL TISSUES
(163) $# CONSTITUTIVELY MACROPINOCYTOSE EXTRA CELLULAR m UID AND TAKE UP !G VIA PHAGOCYTOSIS AND RECEPTOR MEDIATED ENDOCYTOSIS $# EXPRESS SEVERAL RECEPTORS THAT FACILITATE THE INTERNALIZATION AND PRESENTATION OF !G
(164) INCLUDING # TYPE LECTIN RECEPTORS SUCH AS THE MANNOSE RECEPTOR ;= AND $%# ;=
(165) AS WELL AS RECEPTORS FOR THE &C DOMAIN OF IMMUNOGLOBULINS )G &C a2 AND &C¡2
(166) WHICH BIND THE &C DOMAIN OF )G' AND )G%
(167) RESPECTIVELY &URTHERMORE
(168) $# EXPRESS SPECIl C RECEPTORS FOR HEAT SHOCK PROTEINS HSP SUCH AS GP AND HSP
(169) MEDIATING THE INTERNALIZATION OF HSP PEPTIDE COMPLEXES ;= !FTER CAPTURE AND INTERNALIZATION
(170) !G ARE PROTEOLYTICALLY PROCESSED INTO AMINO ACID LONG . FRAGMENTS THAT BIND TO -(# CLASS )) MOLECULES FOR PRESENTATION TO #$ 4 LYMPHOCYTES ;= )T IS CURRENTLY BELIEVED THAT LOADING OF -(# CLASS )) MOLECULES WITH PEPTIDE OCCURS IN A SPECIALIZED COMPARTMENT THAT IS LOCATED AT THE INTERSECTION OF THE BIOSYNTHETIC ROUTE OF THE -(# CLASS )) MOLECULES AND THE ENDOCYTIC PATHWAY 4HE -(# CLASS )) MOLECULE CONSTISTS OF AN _ AND A ` CHAIN
(171) THAT ASSOCIATE IN THE ENDOPLASMIC RETICULUM %2 WITH THE K$A INVARIANT CHAIN )I 4HE _`)I COMPLEX EXISTS AS A NINE SUBUNIT TRANSMEMBRANE PROTEIN THAT CONTAINS THREE _` DIMERS ASSOCIATED WITH AN )I TRIMER ! SHORT INTERNAL FRAGMENT OF THE )I
(172) CALLED THE CLASS )) ASSOCIATED INVARIANT CHAIN PEPTIDE #,)0
(173) OCCLUDES OR CLOSES THE CLASS )) PEPTIDE BINDING SITE
(174) THEREBY AVOIDING PRESENTATION OF PEPTIDES PRESENT IN THE %2 4HE _`)I TRIMERS ARE TRANSPORTED VIA THE 'OLGI STACKS TO THE TRANS 'OLGI RETICULUM 4'2 4HERE THE MAJORITY OF ALL THE _`)I TRIMERS ARE SORTED TO SPECIALIZED ENDOCYTIC COMPARTMENTS
(175) WHICH ARE ENRICHED FOR -(# CLASS )) MOLECULES -))# 4HE MAJORITY OF INTRACELLULAR -(# CLASS )) MOLECULES RESIDE IN THOSE -))# -))# ARE MULTIVESICULAR BODY -6" LIKE OR CONTAIN MEMBRANE SHEETS SIMILAR TO THOSE PRESENT IN LYSOSOMES OF OTHER CELL TYPES ; = AND CONTAIN THE LYSOSOMAL MARKER PROTEINS ,AMP AND #$ _`)I COMPLEXES ARE TARGETED TO ENDOCYTIC COMPARTMENTS THROUGH A SIGNAL IN THE CYTOPLASMIC TAIL OF )I *UST BEFORE ARRIVING OR AT THIS COMPARTMENT THE )I IS GRADUALLY DEGRADED BY PROTEOLYTIC CLEAVAGE
(176) LEAVING ONLY #,)0 IN THE PEPTIDE BINDING GROOVE OF -(# CLASS )) DIMERS 4HEN THE NON POLYMORPHIC -(# CLASS )) MOLECULES (,! $- IN HUMANS ( - IN THE MOUSE AND (,! $/ ( / IN THE MOUSE CATALYZE THE EXCHANGE OF #,)0 FOR ANTIGENIC PEPTIDES ; = &INALLY
(177) PEPTIDE LOADED -(# MOLECULES ARE DELIVERED TO THE CELL SURFACE ;= !LTERNATIVELY
(178) -(# PEPTIDE COMPLEX FORMATION CAN INVOLVE INTERNALIZED -(# CLASS )) MOLECULES
(179) WHICH EXCHANGE THEIR ASSOCIATED PEPTIDES IN EARLY ENDOCYTIC COMPARTMENTS BEFORE RETURNING TO THE CELL SURFACE ;= %XOSOMES. -(# CLASS )) MOLECULES ARE TRANSPORTED FROM -))# TO THE PLASMA MEMBRANE VIA UNKNOWN PATHWAYS )T WAS RECENTLY SHOWN THAT -))# CAN FUSE DIRECTLY WITH THE PLASMA MEMBRANE 4HIS PROCESS IS RESPONSIBLE FOR DELIVERY OF PART OF THE INTRACELLULAR -(# CLASS )) TO THE CELL SURFACE -))# CONTAIN CHARACTERISTIC INTERNAL MEMBRANE VESICLES WITH -(# CLASS )) EXPOSED ON THEIR SURFACE &USION OF -))# WITH THE PLASMA MEMBRANE RESULTS IN THE RELEASE OF THESE -(# CLASS )) EXPRESSING VESICLES
(180) NAMED EXOSOMES )N ADDITION TO -(# CLASS )) MOLECULES
(181) EXOSOMES HAVE NOW BEEN SHOWN TO EXPRESS OTHER PROTEINS WHICH PLAY A ROLE IN !G PRESENTATION -(# CLASS ) AND CO STIMULATORY MOLECULES )N CONTRAST
(182) )I OR (,! $-
(183) TWO OTHER IMPORTANT PLAYERS IN THE PROCESS OF -(# CLASS )) RESTRICTED !G PRESENTATION
(184) THAT ARE VERY ABUNDANT IN ENDOSOMES AND LYSOSOMES
(185) ARE NOT DETECTED IN EXOSOMES 4HEREFORE
(186) A HIGHLY SPECIl C MECHANISM OF PROTEIN SEGREGATION WITHIN MULTIVESICULAR ENDOSOMES
(187) BETWEEN THE INTERNAL VESICLES AND THE LIMITING EXTERNAL ENDOSOMAL MEMBRANE RESULTS IN THE SELECTIVE . .
(188) 'ENERAL INTRODUCTION. &IGURE (YPOTHETICAL FUNCTION OF EXOSOMES IN VIVO )MMATURE $#
(189) EXPOSED TO !G
(190) IN ADDITION TO PRESENTING !G DERIVED PEPTIDES THEMSELVES
(191) PRODUCE EXOSOMES LOADED WITH PEPTIDES DERIVED FROM THE !G 4HESE PEPTIDE LOADED EXOSOMES MIGRATE AND CAN BIND TO IMMATURE OR MATURE $# IN THE PERIPHERY
(192) DEPENDING ON THE PRESENCE OF A MATURATION STIMULUS $# MIGRATE FROM THE PERIPHERY TO THE DRAINING LYMPH NODE %XOSOMES ON MATURE $# MAY INDUCE 4 CELL PRIMING IN THE DRAINING LYMPH NODE
(193) WHEREAS EXOSOMES ON IMMATURE $# MAY INDUCE 4 CELL TOLERANCE !G EXPOSED $# MAY ALSO EXCHANGE PEPTIDE LOADED EXOSOMES WITH NON !G EXPOSED $# IN THE LYMPH NODE. ENRICHMENT OF CERTAIN PROTEINS IN EXOSOMES )N ADDITION TO -(# CLASS ) AND )) AND "
(194) EXOSOMES EXPRESS INTEGRINS
(195) )G FAMILY MEMBERS
(196) TETRASPANINS
(197) HEAT SHOCK PROTEINS
(198) CYTOSKELETAL PROTEINS AND PROTEINS THAT PLAY A ROLE IN MEMBRANE TRANSPORT AND FUSION
(199) SIGNAL TRANSDUCTION OR METABOLISM ; = 4HE OLIGOMER FORMING TETRASPAN PROTEINS HAVE BEEN IMPLICATED IN !G PRESENTATION
(200) 4 CELL SIGNALING
(201) 4 CELL ACTIVATION
(202) CELL MOTILITY AND ADHESION
(203) AND FORM COMPLEXES NOT ONLY WITH ONE ANOTHER ; =
(204) BUT ALSO WITH (,! $2 ;=
(205) -(# CLASS ) ;=
(206) INTEGRINS ;= AND THE 4 CELL CORECEPTORS #$ AND #$ ;= 3UCH LARGE PROTEIN NETWORKS MIGHT LIMIT THE DIFFUSION OF MOLECULES SUCH AS -(# CLASS )) AND (,! $-
(207) THEREBY FACILITATING INTERMOLECULAR INTERACTIONS &URTHERMORE
(208) EXOSOMES ARE ENRICHED IN CHOLESTEROL
(209) SPHINGOMYELIN AND GANGLIOSIDE
(210) LIPIDS THAT ARE TYPICALLY ENRICHED IN DETERGENT RESISTANT MEMBRANES OR RAFTS 2ECRUITMENT OF MEMBRANE PROTEINS FROM THE -))# LIMITING MEMBRANE TO THE INTERNAL VESICLES MAY OCCUR VIA THEIR INCORPORATION INTO TETRASPANIN CONTAINING RAFTS ;= 4HE DEl NITION BY PROTEOMIC STUDIES OF A SUBSET OF CELLULAR PROTEINS THAT ARE TARGETED SPECIl CALLY TO EXOSOMES CLEARLY SHOWS THAT EXOSOMES ARE DISTINCT FROM THE MICROVESICLES THAT ARE PRODUCED BY APOPTOTIC CELLS AND THAT THEY ARE ONLY SECRETED BY LIVING CELLS ;= !LTHOUGH THE PHYSIOLOGICAL TARGETS AND FUNCTIONS OF !0# DERIVED EXOSOMES REMAIN LARGELY TO BE RESOLVED
(211) FOLLICULAR $# &$# PRESENT IN THE GERMINAL CENTERS OF SECONDARY LYMPHOID ORGANS HAVE RECENTLY BEEN SHOWN TO BIND " LYMPHOCYTE DERIVED EXOSOMES AT THEIR SURFACE
(212) WHICH SUPPORTS THE NOTION THAT !0# DERIVED EXOSOMES PLAY AN IMMUNOREGULATORY ROLE ;= 7HEREAS !G !B COMPLEXES RETAINED BY &$# ARE PIVOTAL FOR SELECTION OF HIGH AFl NITY " LYMPHOCYTES
(213) EXOSOMES DOCKED ON &$# MIGHT SELECT AND RECRUIT SPECIl C 4H CELLS )N THIS WAY
(214) &$# MIGHT SIEVE AND FACILITATE THE INTERACTION BETWEEN MATCHING " AND 4 CELLS
(215) ULTIMATELY LEADING TO ISOTYPE SWITCHING AND DIFFERENTIATION OF " LYMPHOCYTES INTO PLASMA CELLS OR MEMORY CELLS &URTHERMORE
(216) IN VITRO AND IN VIVO STUDIES WITH ISOLATED EXOSOMES SHOWED THAT !G LOADED EXOSOMES STIMULATE MURINE #$ 4 CELL CLONES ;=
(217) THAT TUMOR PEPTIDE LOADED EXOSOMES INDUCE REJECTION OF ESTABLISHED MOUSE TUMORS ;= AND THAT EXOSOMES BEARING AN ( 9 PEPTIDE ACTIVATE SPECIl C NAÕVE 4 CELLS IN VIVO ;= 4HE PRESENCE OF $# IS REQUIRED IN VITRO TO OBTAIN EFl CIENT !G PRESENTATION TO 4 CELLS BY EXOSOMES ;= !LTHOUGH EXOSOMES ARE IMMUNOGENIC IN THE EXPERIMENTAL SETTINGS REPORTED ABOVE
(218) IT REMAINS TO BE DETERMINED WHETHER 4 CELL STIMULATION BY !0# DERIVED EXOSOMES MIGHT ALSO INDUCE TOLERANCE %XOSOMES ARE PRODUCED NOT ONLY BY !0#
(219) BUT ALSO BY RETICULOCYTES TO DISCARD MEMBRANE PROTEINS ;=
(220) VARIOUS HEMATOPOIETIC CELLS ; =
(221) TUMOR CELLS ;= AND EPITHELIAL CELLS ;= )NDEED
(222) EXOSOMES OR hTOLEROSOMESv PRODUCED BY /6! LOADED RAT EPITHELIAL CELLS INDUCED SOME DEGREE OF !G SPECIl C TOLERANCE ;= . .
(223) #HAPTER . !S SUGGESTED RECENTLY
(224) EXOSOMES MAY PLAY A ROLE IN SPREADING !G SPECIl C SIGNALS
(225) BY EXCHANGING BOTH !G AND -(#PEPTIDE COMPLEXES BETWEEN DIFFERENT $# %XOSOMES MAY FUNCTION IN INTERCELLULAR COMMUNICATION BETWEEN CELLS OF THE IMMUNE SYSTEM 4HE USE OF SMALL VESICLES FOR COMMUNICATIONSIGNALLING BETWEEN CELLS IS ALSO EXPLOITED IN THE CENTRAL NERVOUS SYSTEM
(226) WHERE SYNAPTIC VESICLES ARE SECRETED BY ONE NEURON
(227) TO SIGNAL TO THE OTHER &IGURE SHOWS A MODEL FOR THE HYPOTHETICAL FUNCTION OF EXOSOMES IN VIVO 2EGARDLESS OF THEIR PUTATIVE PHYSIOLOGICAL ROLE
(228) EXOSOMES HAVE THE POTENTIAL TO BE USED AS TOOLS FOR VACCINATION )NDUCTION OF TUMOR PROTECTION BY EXOSOMES SECRETED BY BONE MARROW DERIVED $# PULSED WITH TUMOR PEPTIDES HAS BEEN SHOWN ;= /N THE BASIS OF THESE RESULTS
(229) THE USE OF EXOSOMES FOR THE IMMUNOTHERAPY OF CANCER PATIENTS WAS UNDERTAKEN 4WO PHASE ) TRIALS WERE STARTED RECENTLY
(230) ONE USING -!'% EPITOPE LOADED $# DERIVED EXOSOMES IN PATIENTS WITH METASTATIC MELANOMA
(231) THE OTHER USING $# DERIVED -!'% PEPTIDE LOADED EXOSOMES IN UNRESECTABLE NON SMALL CELL LUNG CARCINOMA PATIENTS %XOSOMES HAVE BEEN PROVEN TO BE A SAFE VACCINE IN THESE PATIENTS )N ADDITION TO $# DERIVED EXOSOMES
(232) TUMOR DERIVED EXOSOMES ARE USED IN CLINICAL TRIALS 4UMOR DERIVED EXOSOMES CONTAIN TUMOR !G
(233) WHICH ARE PRESENTED TO -(# CLASS ) RESTRICTED 4 CELL CLONES IN VITRO
(234) AFTER EXOSOME LOADING ONTO $# ;= 2ECENTLY
(235) MALIGNANT EFFUSIONS FROM CANCER PATIENTS HAVE BEEN FOUND TO CONTAIN EXOSOMES 4UMOR DERIVED EXOSOMES WERE ISOLATED FROM ASCITES OF PATIENTS WITH PERITONEAL OR PLEURAL CARCINOMATOSIS ASSOCIATED WITH ASCITIS OR PLEURAL EFFUSIONS WHO HAD TUMOR CELLS IN THE BIOLOGICAL m UID 4HESE EXOSOMES HAVE BEEN SHOWN TO DELIVER TUMOR !G TO MONOCYTE DERIVED $# IN VITRO ,YMPHOCYTES SPECIl C TO THE TUMOR COULD BE EXPANDED FROM PERIPHERAL BLOOD CELLS BY PULSING $# WITH ASCITES EXOSOMES ;= 0RESENTATION OF ENDOGENOUS ANTIGENS IN -(# CLASS ). )N HIGHER ORGANISMS
(236) -(# CLASS ) MOLECULES ARE EXPRESSED ON THE SURFACE OF VIRTUALLY ALL . NUCLEATED CELLS
(237) WHERE THEY PRESENT !G TO #$ 4 CELLS ;= 3HORTLY AFTER SYNTHESIS IN THE %2 THE -(# CLASS ) HEAVY CHAIN ASSOCIATES NON COVALENTLY WITH A NON POLYMORPHIC LIGHT CHAIN
(238) TERMED ` MICROGLOBULIN
(239) AND -(# CLASS ) MOLECULES ARE LOADED WITH PEPTIDE IN THE %2 -OST OF THESE PEPTIDES ARE DERIVED FROM CYTOSOLIC PROTEINS ;= !G PROCESSING STARTS BY UBIQUITIN CONJUGATION ;= IN THE CYTOSOL 5BIQUITINATED PROTEINS ARE DEGRADED BY THE PROTEASOME
(240) A MULTISUBUNIT PROTEOLYTIC COMPLEX
(241) IN AN !40 DEPENDENT FASHION !FTER PEPTIDES ARE GENERATED IN THE CYTOSOL
(242) THEY ARE TRANSLOCATED ACROSS THE %2 MEMBRANE BY THE TRANSPORTER ASSOCIATED WITH !G PRESENTATION 4!0 ;= AND LOADED ONTO NEWLY SYNTHESIZED -(# CLASS ) MOLECULES WITHIN THE %2 ;= 4!0 IS A HETERODIMER COMPOSED OF TWO SUBUNITS
(243) 4!0 AND 4!0
(244) EACH CONTAINING AN . TERMINAL HYDROPHOBIC REGION WITH MULTIPLE PREDICTED TRANSMEMBRANE DOMAINS
(245) AND A CYTOSOLIC # TERMINAL !40 BINDING DOMAIN %XPRESSION OF BOTH 4!0 AND 4!0 IS REQUIRED TO GET EFl CIENT BINDING
(246) CERTAIN PEPTIDES BIND PREFERENTIALLY TO 4!0 WHILE OTHERS BIND PREFERENTIALLY TO 4!0 0EPTIDE BINDING IS !40 INDEPENDENT
(247) WHILE TRANSLOCATION IS !40 DEPENDENT ;= 4HE DEGRADATION OF CYTOSOLIC !G IS AN ESSENTIAL STEP IN THE GENERATION OF MOST -(# CLASS ) PRESENTED EPITOPES #YTOSOLIC PROTEIN DEGRADATION IS HIGHLY SPECIl C AND TIGHTLY REGULATED TO PREVENT NONSPECIl C DESTRUCTION OF ESSENTIAL SELF PROTEINS $EGRADATION OF CYTOSOLIC !G AND GENERATION OF -(# CLASS ) ASSOCIATED EPITOPES SHOULD BE RAPID
(248) TO DETECT RAPIDLY REPLICATING PATHOGENS
(249) AND EFl CIENT
(250) TO PRESENT SUFl CIENT NUMBERS OF EPITOPES FROM SMALL AMOUNTS OF !G 7HILE EFl CIENT PEPTIDE GENERATION IS DESIRABLE THE PROTEIN DEGRADATION PATHWAY MUST REMAIN SUFl CIENTLY GENERAL TO ACCOMMODATE A PLETHORA OF FOREIGN !G ;=. .
(251) 'ENERAL INTRODUCTION. &IGURE 3CHEMATIC REPRESENTATION OF PROPERTIES OF IMMATURE AND MATURE $# $# MATURATION CAN BE INDUCED BY DIFFERENT STIMULI
(252) INCLUDING PATHOGEN DERIVED SIGNALS
(253) CYTOKINES AND 4 CELL DERIVED SIGNALS. h#ROSS PRESENTATIONv OF EXOGENOUS ANTIGENS IN -(# CLASS ) )N ADDITION TO AN EXOGENOUS PATHWAY FOR PROCESSING OF -(# CLASS )) RES TRICTED !G AND AN ENDOGENOUS PATHWAY FOR -(# CLASS ) RESTRICTED !G
(254) $# HAVE A SPECIALIZED CAPACITY TO PROCESS EXOGENOUS !G INTO THE -(# CLASS ) PATHWAY ;= 4HIS FUNCTION
(255) KNOWN AS CROSS PRESENTATION
(256) PROVIDES THE IMMUNE SYSTEM WITH AN IMPORTANT MECHANISM FOR GENERATING IMMUNITY TO PATHOGENS THAT AVOID PROFESSIONAL !0# CROSS PRIMING AND TOLERANCE TO SELF !G THAT ARE NOT EXPRESSED BY THE !0# CROSS TOLERANCE ;= )NDUCTION OF 4 CELL TOLERANCE BY CROSS PRESENTATION OF CELLULAR !G OCCURS VIA INDUCTION OF DELETION ; = OR ANERGY ;= 4WO ROUTES FOR THE EXOGENOUS -(# CLASS ) PATHWAY HAVE PREVIOUSLY BEEN DESCRIBED ! 4!0 INDEPENDENT PATHWAY IN WHICH !G IS MOST LIKELY HYDROLYZED IN ENDOSOMES AND LOADED ONTO RECYC LING -(# CLASS ) MOLECULES PRESENT IN THESE COMPARTMENTS HAS BEEN SHOWN ;= !NOTHER POSSIBLE ROUTE FOR LOADING OF PEPTIDES IS A PHAGOSOME TO CYTOSOL PATHWAY THAT IS PROTEASOME AND 4!0 DEPENDENT
(257) RESULTING IN PEPTIDE LOADING IN THE %2 LUMEN AND TRANSPORT OF PEPTIDE LOADED -(# CLASS ) MOLECULES BY THE SECRETORY PATHWAY ;= 2ECENTLY IT WAS SHOWN THAT SOON AFTER OR DURING FORMATION
(258) PHAGOSOMES FUSE WITH THE %2 !FTER EXPORT OF PHAGOCYTOSED !G TO THE CYTOSOL AND DEGRADATION BY ASSOCIATED PROTEASOMES
(259) PEPTIDES ARE RAPIDLY TRANSLOCATED BY 4!0 INTO THE LUMEN OF THE SAME PHAGOSOMES
(260) BEFORE LOADING ON PHAGOSOMAL -(# CLASS ) MOLECULES ; = 4HIS LATTER PATHWAY IS A COMPLETELY NEW CROSS PRESENTATION ROUTE
(261) SINCE IT IS 4!0 DEPENDENT IN CONTRAST TO THE l RST MENTIONED PATHWAY AND PEPTIDE LOADING TAKES PLACE IN THE PHAGOSOME LUMEN INSTEAD OF THE %2 LUMEN IN CONTRAST TO THE SECOND MENTIONED PATHWAY 4RANSLOCATION TO THE CYTOSOL IS SELECTIVE IN THE SENSE THAT THERE IS NO GROSS DISRUPTION OF LYSOSOME COMPARTMENTS AND TRANSLOCATION IS SIZE SELECTIVE ;= 4HE PROTEASOME AND 4!0 DEPENDENT PATHWAY IS THOUGHT TO BE INVOLVED IN IMMUNE RESPONSES AGAINST TRANSPLANTATION !G ;=
(262) PARTICULATE !G ;=
(263) TUMORS ;=
(264) AND VIRUSES ;= )T IS ALSO OPERATIVE IN THE DEVELOPMENT OF TOLERANCE ;= 0RESENTATION OF EXOGENOUS !G IN -(# CLASS ) IN VITRO CAN BE IMPROVED BY COMPLEXING !G TO BEADS ;= OR HEAT SHOCK PROTEINS
(265) BY PROVIDING !G IN BACTERIA ;=
(266) BY ADMINISTERING !G IN APOPTOTIC CELLS OR BY PROVIDING !G IN THE FORM OF !G !B IMMUNE COMPLEXES ;= 4HE RELATIVE CONTRIBUTION OF THE THREE DIFFERENT ROUTES FOR PEPTIDE LOADING ONTO -(# CLASS ) MOLECULES IN VIVO IS UNCLEAR )N VIVO CROSS PRIMING AGAINST TUMOR !G REQUIRES 4!0
(267) SUGGESTING THAT IN THIS CASE THE CLASSIC PHAGOSOME CYTOSOL %2 PATHWAY OR THE %2 PHAGOSOME FUSION PATHWAY PREDOMINANT ;=. .
(268) #HAPTER . %NVIRONMENTAL SIGNALS FOR $# MATURATION )MMATURE VERSUS MATURE DENDRITIC CELLS. 2ECENT STUDIES HAVE DEMONSTRATED A REMARKABLE FUNCTIONAL PLASTICITY OF A GIVEN $# SUBSET TO INDUCE DIFFERENT TYPES OF 4 CELL RESPONSES DEPENDING ON THE TYPE OF INVADING PATHOGENS #ELLS OF THE INNATE IMMUNE SYSTEM RECOGNIZE PATHOGEN SPECIl C MOLECULAR PATTERNS 0!-0 USING 4OLL LIKE RECEPTORS 4,2 4HE RESPONSIVENESS TO A GIVEN 0!-0 HAS BEEN LINKED TO THE EXPRESSION OF A PARTICULAR 4,2 0!-0 SUCH AS ,03
(269) BACTERIAL $.!
(270) AND DOUBLE STRANDED 2.! DS2.!
(271) INDUCE $# MATURATION ;= -OREOVER
(272) $# MATURATION CAN BE INDUCED BY 4 CELL DERIVED SIGNALS
(273) SUCH AS #$, ;=
(274) OR BY !G !B COMPLEXES ;= &URTHERMORE
(275) THE BALANCE BETWEEN PROINm AMMATORY AND ANTI INm AMMATORY SIGNALS IN THE LOCAL MICROENVIRONMENT
(276) INCLUDING 4.&
(277) ),
(278) ),
(279) ),
(280) 4'& `
(281) AND 0'
(282) PLAY A ROLE IN THE MATURATION PROCESS ;= !LL THESE SIGNALS CAN INDUCE IMMATURE $# TO MATURE AND MIGRATE TO THE DRAINING LYMPH NODES WHERE THEY PRESENT CAPTURED !G TO NAÕVE 4 LYMPHOCYTES 4HIS IS ONE OF THE WAYS $# BRIDGE INNATE AND ADAPTIVE IMMUNITY $# MATURATION IS GENERALLY SEEN IN RESPONSE TO PATHOGENS OR HALLMARKS OF THEIR PRESENCE )MMATURE $# ARE SPECIALIZED IN CAPTURING AND PROCESSING !G TO FORM -(# PEPTIDE COMPLEXES $# MATURATION IS ASSOCIATED WITH DECREASED !G UPTAKE AND ACQUISITION OF THE CAPACITY TO EFl CIENT LY PRESENT !G AND PRIME 4 CELL RESPONSES -ATURATION MAY BE SEEN AS A PHYSIOLOGICAL RESPONSE TO INFECTION WITH PROFOUND IMPLICATIONS FOR 4 CELL IMMUNITY -ATURATION OF $# IS REQUIRED FOR EFl CIENT INDUCTION OF PRIMARY 4 CELL RESPONSES 4HE EFl CACY OF $# IN 4 CELL BINDING AND ACTIVATION CANNOT BE ATTRIBUTED TO A SINGLE SPECIl C MOLECULE
(283) BUT MERELY IS THE RESULT OF QUANTITATIVE EFFECTS AND THEIR REGULATION 4HE $# MATURATION PROCESS IS ASSOCIATED WITH SEVERAL COORDINATED EVENTS SUCH AS LOSS OF ENDOCYTICPHAGOCYTIC RECEPTORS UP REGULATION OF -(# MOLECULES AND CO STIMULATORY MOLECULES EG #$
(284) #$
(285) #$
(286) #$
(287) /8 ,
(288) #$
(289) "" , CHANGE IN ADHESION MOLECULE AND CYTOKINE RECEPTOR EXPRESSION AND CYTOKINE PRODUCTION CHANGE IN MORPHOLOGY SHIFT IN LYSOSOMAL COMPARTMENTS WITH DOWN REGULATION OF #$ AND UPREGULATION OF $# LYSOSOME ASSOCIATED MEMBRANE PROTEIN $# ,!-0 AND CHANGE IN -(# CLASS )) ENRICHED COMPARTMENTS -))# ;= $EPENDING ON THE CONDITIONS
(290) $# CAN STIMULATE THE OUTGROWTH AND ACTIVATION OF A VARIETY OF 4 CELLS
(291) WHICH AFFECT THE IMMUNE RESPONSE DIFFERENTLY )N RESPONSE TO MATURATION SIGNALS $# UP REGULATE ##2
(292) A HOMING RECEPTOR
(293) TO MIGRATE TO THE LYMPH NODE ; = &IGURE SHOWS IMMATURE AND MATURE $# PROPERTIES. )NNATE IMMUNITY MATURATION SIGNALS )NNATE IMMUNE RECOGNITION OF INVADING PATHOGENS IS MEDIATED BY A SET OF RECEPTORS THAT HAVE EVOLVED TO RECOGNIZE CONSERVED MOLECULAR PATTERNS SHARED BY LARGE GROUP OF PATHOGENS ;= !CCUMULATING EVIDENCE HAS SHOWN THAT THIS RECOGNITION CAN BE ATTRIBUTED MAINLY TO THE 4,2 FAMILY ; = 4,2 ARE ANCIENT MICROBIAL PATTERN RECOGNITION RECEPTORS HIGHLY CONSERVED FROM $ROSOPHILA TO HUMANS ;= 2ECENTLY
(294) THE HUMAN 4OLL), RECEPTOR LIKE PROTEINS
(295) WHICH ARE HOMOLOGUES OF THE $ROSOPHILA 4OLL MOLECULE
(296) WERE IDENTIl ED 4,2 ARE TYPE ) TRANSMEMBRANE PROTEINS THAT HAVE A LEUCINE RICH REPEAT DOMAIN IN THE EXTRACELLULAR REGION AND CYTOPLASMIC DOMAINS
(297) THE 4OLL), RECEPTOR HOMOLOGY DOMAIN 4)2 ;=
(298) THAT SHARE SEQUENCE SIMILARITY WITH THE CYTOPLASMIC DOMAIN OF THE HUMAN ), RECEPTOR 4HE 4,2 MOLECULES MEDIATE SIGNALING THROUGH THE ADAPTOR MOLECULES -Y$
(299) ), RECEPTOR ASSOCIATED KINASE )2!+
(300) AND 4.& RECEPTOR ASSOCIATED FACTOR 42!& ;= 4HIS ACTIVATES THE .& g" PATHWAY AND MITOGEN ACTIVATED PROTEIN KINASES -!0+ ;=
(301) THEREBY REGULATING THE EXPRESSION OF THE CO STIMULATORY MOLECULE #$ " AS WELL AS THE EXPRESSION OF A NUMBER OF INm AMMATORY CYTOKINES ;= )N PARTICULAR
(302) INDUCTION OF ), IN RESPONSE TO MICROBIAL LIPOPROTEINS IS MEDIATED BY 4,2 ;= 4O DATE
(303) TEN . .
(304) 'ENERAL INTRODUCTION. HUMAN AND NINE MURINE TRANSMEMBRANE PROTEINS HAVE BEEN SHOWN TO BELONG TO THE MAMMALIAN 4,2 FAMILY 4HE TWO $# SUBSETS OF HUMAN PERIPHERAL BLOOD
(305) - $# AND 0 $#
(306) ARE DEMONSTRATED TO EXPRESS A DIFFERENT SET OF 4,2 - $# EXPRESS ALL 4,2 EXCEPT 4,2 AND 4,2
(307) WHICH ARE SELEC TIVELY EXPRESSED BY 0 $# ;= 0 $# IN CONTRAST
(308) DO NOT EXPRESS 4,2 )N CONTRAST TO THE DICHOTOMY IN 4,2 EXPRESSION ON 0 $# AND - $# IN HUMANS
(309) M2.! FOR MOST 4,2 IS EXPRESSED AT SIMILAR LEVELS BY MURINE SPLENIC $# SUBTYPES
(310) INCLUDING 0 $# 4,2 IS PREFERENTIALLY EXPRESSED BY , $#
(311) WHILE 4,2 AND 4,2 ARE ABSENT FROM THIS SUBSET ;= 4ABLE )) SHOWS THE DIFFERENT 4,2
(312) THEIR LIGANDS AND THEIR EXPRESSION PATTERNS ON HUMAN AND MOUSE $# SUBSETS -ICROBIAL MOLECULES THAT TRIGGER 4,2
(313) 4,2
(314) 4,2
(315) 4,2 AND 4,2 HAVE BEEN IDENTIl ED 0EPTIDOGLYCAN AND MYCOBACTERIA BIND TO AND SIGNAL VIA 4,2 ; = 0OLYINOSINE POLYCITIDYLIC ACID 0OLY )#
(316) A VIRAL DS2.! LIKE MOLECULE
(317) SIGNALS THROUGH 4,2 DS2.! IS ABLE TO DIFFERENTIATE AND ACTIVATE $# 4HIS RESULTS IN A RAPID PRODUCTION OF TYPE ) )&. LEADING TO EXPRESSION OF -X!
(318) A PROTEIN THAT PROTECTS THE $# FROM THE LETHAL EFFECT OF THE VIRUS ;= 5PON EXPOSURE TO ,03 THE EXPRESSION OF 4,2 IS INHIBITED 4HIS MIGHT REPRESENT A REGULATORY MECHANISM AFTER $# HAVE ENCOUNTERED PATHOGENS ;= 0OLY )# INDUCES STABLE MATURATION OF HU MAN $# WITH HIGH EXPRESSION LEVELS OF (,! $2
(319) #$
(320) AND THE $# MATURATION MARKER #$ ;= )N ADDITION
(321) POLY )# TREATED $# DOWNREGULATE PINOCYTOSIS
(322) PRODUCE HIGH LEVELS OF ), AND LOW LEVELS OF ),
(323) INDUCE STRONG 4 CELL PROLIFERATION
(324) AND EFFECTIVELY PRESENT PEPTIDE !G TO -(# CLASS ) RESTRICTED #4, ,03 FROM 'RAM NEGATIVE BACTERIA SIGNALS THROUGH 4,2 ,03 IS PROBABLY THE MOST POWERFUL MICROBIAL STIMULANT OF INNATE IMMUNE RESPONSES ,03 CAN PROVOKE A VARIETY OF IMMUNOSTIMULATORY RESPONSES
(325) FOR EXAMPLE PRODUCTION OF INm AMMATORY CYTOKINES SUCH AS ),
(326) 4.& _ AND ), ;=
(327) AND INm AMMATORY EFFECTOR SUBSTANCES SUCH AS NITRIC OXIDE ;= 4HESE BIOLOGICAL ACTIVITIES CAN BE ASCRIBED TO THE LIPID ! PORTION OF ,03 4,2 IS A PART OF TRIMOLECULAR ,03 RECEPTOR COMPLEX ;= THAT CONTAINS TWO CORECEPTORS -$
(328) WHICH IS REQUIRED FOR 4,2 FUNCTION ;=
(329) AND #$ ;=
(330) WHICH IS A HIGH AFl NITY '0) LINKED ,03 BINDING PROTEIN 4HE STRUCTURE OF THE PROINm AMMATORY COMPONENT OF ,03
(331) LIPID ! ;=
(332) VARIES BETWEEN BACTERIA OF DIFFERENT SPECIES $OWNSTREAM FROM 4,2
(333) -Y$ HAS BEEN IDENTIl ED AS A MEDIATOR OF ,03 SIGNAL TRANSDUCTION ;= . 4ABLE )) %XPRESSION OF 4OLL LIKE RECEPTORS ON HUMAN AND MOUSE $# SUBSETS %XPRESSION LEVELS ARE INDICATED AS DESCRIBED IN THE LEGEND OF 4ABLE ) ,IGANDS FOR THE DIFFERENT 4OLL LIKE RECEPTORS ARE INDICATED 4ABLE )) 4OLL LIKE RECEPTOR 4,2 4,2 4,2 4,2 4,2 4,2 4,2 4,2 4,2 4,2. ,IGAND 0!-0. 0EPTIDOGLYCANMYCOBACTERIA ,IPOTHEICHOIC ACIDS 0OLY )# ,03LIPOTHEICOIC ACIDS &LAGELLIN )MIQUIDAZOQUINOLINES 5NMETHYLATED #P' $.!. - $#. 0 $#. , $#. ¢ . EXPRESSION ON HUMAN MYELOID $# - $# EXPRESSION ON MURINE - $#. EXPRESSION ON HUMAN PLASMACYTOID $# 0 $# EXPRESSION ON MURINE 0 $#. EXPRESSION ON MURINE LYMPHOID $# , $# . . .
(334) #HAPTER . -AMMALIAN 4,2 RECOGNIZES BACTERIAL m AGELLIN FROM BOTH 'RAM POSITIVE AND 'RAM NEGATIVE BACTERIA ;= !CTIVATION OF THIS RECEPTOR MOBILIZES THE NUCLEAR FACTOR .& g" AND STIMULATES 4.& _ PRODUCTION "ACTERIAL $.! CONTAINING UNMETHYLATED #P' MOTIFS SIGNALS THROUGH 4,2
(335) RESULTING IN THE PRODUCTION OF )&. _ ;= 4HE KEY FEATURE THAT DISTINGUISHES MAMMALIAN FROM BACTERIAL $.! IS THAT #P' MOTIFS IN BACTERIAL $.! ARE UNMETHYLATED ;= 4HUS
(336) THE VERTEBRATE IMMUNE SYSTEM HAS EVOLVED A SPECIl C 4,2 THAT DISTINGUISHES BACTERIAL $.! FROM SELF $.! ;= 3YNTHETIC #P' CONTAINING OLIGODEOXYNUCLEOTIDE #P' /$. MIMICS THE STIMULATORY EFFECT OF BACTERIAL $.! ;= #P' /$. ACTS AS AN ADJUVANT FOR $# AND INDUCES 4H TYPE RESPONSES MOST PROBABLY BY THE DIRECT INDUCTION OF ), AND UPREGULATION OF CO STIMULATORY MOLECULES ;= )N HUMANS
(337) 4,2 IS SELECTIVELY EXPRESSED ON 0 $# ;= #P' $.! CAN INDUCE CYTOKINE PRODUCTION FROM 0 $#
(338) BUT NOT FROM - $# ;= #P' $.! MUST BE INTERNALIZED IN ORDER TO STIMULATE CELLS 4HE CELLULAR UPTAKE OF #P' IS PRESUMABLY FOLLOWED BY THEIR INTERACTION WITH AN INTRACELLULAR RECEPTOR 4HE INTRACELLULAR LOCATION OF THE #P' RECEPTOR SUGGESTS THAT IMMUNE RECOGNITION OF #P' $.! MAY HAVE EVOLVED AS A DEFENSE AGAINST INTRACELLULAR BACTERIA
(339) VIRUSES
(340) AND RETROVIRUSES 4HUS
(341) PATHOGEN RECOGNITION BY 4,2 PROVOKES RAPID ACTIVATION OF INNATE IMMUNITY BY INDUCING PRODUCTION OF PROINm AMMATORY CYTOKINES AND UP REGULATION OF CO STIMULATORY MOLECULES ;= !CTIVATED INNATE IMMUNITY SUBSEQUENTLY LEADS TO EFFECTIVE ADAPTIVE IMMUNITY )N THIS REGARD
(342) THE 4,2 ARE CONSIDERED TO BE ADJUVANT RECEPTORS $IFFERENT 4,2 CAN EXERT DISTINCT
(343) BUT OVERLAPPING SETS OF BIOLOGICAL EFFECTS ;= 4,2 SHARE A NUMBER OF COMMON SIGNALING FEATURES SUCH AS )2!+ AND -Y$
(344) BUT ALSO EXHIBIT SUBSTANTIAL DIFFERENCES IN CO FACTOR REQUIREMENTS THAT RESULT IN RELATIVELY UNIQUE SIGNALING MECHANISMS &URTHERMORE
(345) IT IS LIKELY THAT 4,2 CROSS TALK HAS A PROFOUND IMPACT ON THE ABILITY OF A CELL TO RESPOND OVER A PROTRACTED PERIOD TO DIVERSE MICROBIAL PRODUCTS ;=. !DAPTIVE IMMUNITY MATURATION SIGNALS #$ #$, INTERACTIONS. #$ IS A MEMBER OF THE 4.& 2 SUPERFAMILY THAT PLAYS A CRITICAL ROLE IN BOTH HUMORAL AND CELLULAR IMMUNE RESPONSES ;= )T WAS INITIALLY SHOWN TO BE CONSTITUTIVELY EXPRESSED ON THE MAJORITY OF " CELLSBUT HAS SINCE BEEN FOUND TO BE EXPRESSED ON A WIDE RANGE OF CELLS
(346) INCLUDING EPITHELIALAND ENDOTHELIAL CELLS AND ON ALL !0# ; = 4HE NATURAL LIGAND FOR #$
(347) #$#$,
(348) IS A TRIMERIC 4.& LIKE MOLECULE THAT IS EXPRESSED MAINLY ON ACTIVATED 4H CELLS ;= ,IGATION OF #$ ON $# INDUCES MATURATION
(349) REm ECTED IN PRODUCTION OF HIGH LEVELS OF ),
(350) ENHANCED 4 CELL STIMULATORY CAPACITY AND IMPROVED $# SURVIVAL 4RIGGERING #$ ON $# . EMPOWERS THESE CELLS TO ACTIVATE NAIVE #$ #4, ;= 3UCH CONDITIONING OR LICENSINGOF $# CAN BE ACHIEVED BY #$ EXPRESSING 4 HELPER CELLS
(351) BY SOLUBLE #$, TRIMERS OR #$ MONOCLONAL !B M!B ;= !0# ACTIVATION THROUGH #$ #$, INTERACTIONS REPRESENTS A CRUCIAL IMMUNOREGULATORY STEP FOR THE ESTABLISHMENT OF PROTECTIVE 4 CELL IMMUNITY AGAINST PATHOGENS AND TUMORS ;= - $# ARE KNOWN TO MATURE INTO THE MOST POTENT HUMAN 4H TYPE INDUCING !0# UPON #$ LIGATION ;= )T HAS BEEN SHOWN THAT #$, HAS DIFFERENT EFFECTS ON THE DIFFERENT BLOOD $# SUBSETS )T APPEARS THAT 0 $# ACTIVATED BY #$, INDUCE 4H DIFFERENTIATION
(352) WHEREAS - $# ACTIVATED BY #$, INDUCE . 4H DIFFERENTIATION ;= #$ LIGATION BYPASSES THE NEED FOR #$ 4 CELL HELP ;= !NTIGEN ANTIBODY COMPLEXES AND &C RECEPTORS. )N ADDITION TO MICROBIAL AND INm AMMATORY PRODUCTS AS WELL AS #$ 4H DEPENDENT #$ LIGATION
(353) !G !B IMMUNE COMPLEXES )# ARE ABLE TO INDUCE $# MATURATION IN VITRO ;= 4HIS . ENABLES $# TO PRIME PEPTIDE SPECIl C #$ #4, IN VIVO
(354) INDEPENDENTLYOF #$ 4H CELLS ;= . .
(355) 'ENERAL INTRODUCTION. $# EXPRESS SEVERAL RECEPTORS THAT FACILITATE THE INTERNALIZATION AND PRESENTATION OF !G
(356) INCLUDING # TYPE LECTIN RECEPTORS SUCHAS THE MANNOSE RECEPTOR AND $%#
(357) AS WELL AS RECEPTORS FOR THE &C DOMAIN OF )G &Ca2 AND &C¡2
(358) WHICH BIND THE &C DOMAINOF )G' AND )G%
(359) RESPECTIVELY ;= 4HREE CLASSES OF &C a2 HAVE BEEN RECOGNIZED TO DATE &C a2)
(360) &Ca2)) AND &Ca2))) %ACH CLASS OF &C a2 CONSTISTS OF SEVERAL INDIVIDUAL RECEPTOR ISOFORMS ;= &C a2) IS A HIGH AFl NITY RECEPTOR CAPABLE OF BINDING MONOMERIC )G' &Ca2)) AND &Ca2))) ARE LOW AFl NITY RECEPTORS
(361) CAPABLE OF BINDING ONLY MULTIMERIC )G' 4HEY ARE STRUCTURALLY RELATED RECEPTORS
(362) WITH EITHER TWO &Ca2)) AND &Ca2))) OR THREE &Ca2) )G LIKE EXTRACELLULAR DOMAINS
(363) A SINGLE TRANSMEMBRANE DOMAIN AND CYTOPLASMIC REGIONS OF VARIABLE LENGTH 4HE l RST EXTRACELLULAR )G LIKE DOMAIN AND PART OF THE SECOND ONE OF &C a2) ARE HIGHLY HOMOLOGOUS WITH THE CORRESPONDING DOMAINS OF THE LOW AFl NITY RECEPTORS
(364) WHILE THE THIRD )G LIKE EXTRACELLULAR DOMAIN ACCOUNTS FOR THE UNIQUE ABILITY OF THIS RECEPTOR TO BIND MONOMERIC )G' ;= &UNCTIONALLY &C a2 CAN BE DIVIDED IN TWO GROUPS ACTIVATING &Ca2 HUMAN &Ca2)A
(365) ))A AND n)))A
(366) MURINE &C a2) AND n))) AND INHIBITING &Ca2 HUMAN &Ca2))B AND nB
(367) MURINE &C a2))B AND nB 7ITH THE EXCEPTION OF &C a2))A
(368) THE ACTIVATING RECEPTORS ARE ASSOCIATED WITH VARIOUS SUBUNITS a
(369) c AND ` CHAINS THAT CONTAIN ONE OR MORE CYTOPLASMIC IMMUNO RECEPTOR TYROSINE BASED ACTIVATION MOTIFS )4!-
(370) WHICH ARE CONSERVED AMONG A NUMBER OF ACTIVATING RECEPTORS
(371) LIKE THE " CELL AND 4 CELL RECEPTORS 4HE SINGLE CHAIN &Ca2))A CONTAINS A SINGLE )4!- MOTIF IN ITS CYTOPLASMIC TAIL 4HE INHIBITING RECEPTORS
(372) IN CONTRAST
(373) CONTAIN AN IMMUNO RECEPTOR TYROSINE BASED INHIBITION MOTIF )4)- IN THEIR INTRACELLU LAR REGION (UMAN BLOOD $# EXPRESS SEVERAL TYPES OF &C a2
(374) INCLUDING TYPE) &Ca2)
(375) #$ AND TYPE )) &C a2))
(376) #$ ;= -URINE SPLEEN OR BONE MARROW DERIVED $# EXPRESS ALL THREE &C a2 &Ca2)
(377) &Ca2)) AND &Ca2))) #$ ;= &Ca2 BIND )# WITH VERY HIGH AFl NITY AND MAY BE FUNCTIONALLY CONSIDERED AS !G RECEPTORS 4ARGETING !G TO &C a2 PROMOTES CROSS PRESENTATION BY SEVERAL ORDERS OF MAGNITUDE IN $# 4HE &Ca2 MEDIATED CROSS PRIMING PATHWAY REQUIRES THE 4!0 4!0 TRANSPORTER AND IS SENSITIVE TO LACTACYSTIN
(378) A PROTEASOME INHIBITOR
(379) INDICATING THAT AFTER INTERNALIZATION
(380) )G' COMPLEXED !G ARE TRANSFERRED INTO THECYTOSOL AND REACH THE CONVENTIONAL -(# CLASS ) !G PRESENTATION PATHWAY ;= &Ca2 ENGAGEMENT INDUCES FULL $# MATURATION
(381) REm ECTED BY INCREASED LEVELS OF -(# AND CO STIMULATORY MOLECULES #$
(382) #$
(383) AND #$ AT THE CELL SURFACE AND PRODUCTION OF HIGH LEVELS OF ), &C a2 MEDIATED INTERNALIZATION OF )# BY $# FULl LLS A DUAL ROLE IN 4 CELL PRIMING TO EXOGENOUS !G ENHANCEMENT OF !G UPTAKE BY $# AND ACTIVATION OF $#
(384) RESULTING IN hLICENCE TO KILLv ;= 3IMULTANEOUS INDUCTION OFMATURATION AND -(# CLASS ) AND CLASS )) RESTRICTED PRESENTATION BY A SINGLE RECEPTOR LIGAND INTERACTION SHOULD RESULT IN EFl CIENT 4 CELL PRIMING IN VIVO ;= 4HUS
(385) THE PRESENCE OF SPECIl C !B CAN CRUCIALLY AFFECT THE INDUCTION OF CELLULAR RESPONSES. $ENDRITIC CELL MIGRATION 5PON ACTIVATION
(386) $# TRAVEL TO THE LYMPHOID ORGANS SUCH AS THE SPLEEN AND THE LYMPH NODES 4HERE
(387) $# ATTRACT 4 AND " CELLS BY RELEASING CHEMOKINES AND MAINTAIN THE VIABILITY OF RECIRCULATING 4 LYMPHOCYTES ;= -IGRATION OF $# IS TIGHTLY REGULATED AS A FUNCTION OF MATURATION ;= ! VARIETY OF CYTOKINES AND CHEMOKINES EG '- #3&
(388) 4.& _
(389) ),
(390) -)0 _ AND ` MODULATE $# MOVEMENT AND MATURATION 4HE SPECIl C EFFECTS OF CHEMOKINES ON TARGET CELLS ARE MEDIATED THROUGH SPECIl C SERPENTINE RECEPTORS THAT BELONG TO THE SEVEN TRANSMEMBRANE
(391) ' PROTEIN COUPLED RECEPTOR '0#2 SUPERFAMILY
(392) BUT HAVE UNIQUE STRUCTURAL FEATURES DIFFERENT FROM OTHER '0#2 ;= )N RESPONSE TO THE APPROPRIATE STIMULI $# UP REGULATE ## CHEMOKINE RECEPTOR ##2 ALSO DESIGNATED AS %")
(393) A RECEPTOR THAT DRIVES $# MIGRATION TO THE LYMPHOID VESSELS AND 4 CELL AREAS OF SECONDARY LYMPHOID ORGANS ;= )N THE 4 CELL AREAS $# PRODUCE CHEMOKINES SUCH AS $# #+ AND -$#
(394) WHICH CHEMOATTRACT NAÕVE AND MEMORY 4 CELLS
(395) RESPECTIVELY ; = )N RESPONSE TO ,03
(396) - $# UP REGULATE ##2 AND DOWN REGULATE ##2 EXPRESSION 5PON . .
(397) #HAPTER . VIRUS INFECTION OR EXPOSURE TO BACTERIAL $.! #P' 0 $# UPREGULATE ##2 AND DOWNREGULATE #8# CHEMOKINE RECEPTOR #8#2 "OTH $# SUBSETS RESPOND TO #$, BY UPREGULATION OF ##2 3WITCH IN CHEMOKINE RECEPTOR EXPRESSION IS ACCOMPANIED BY UPREGULATION OF "
(398) "
(399) #$ AND (,! $2 )NTERESTINGLY
(400) THE EXTENT OF ##2 UPREGULATION IS CONSISTENTLY MUCH HIGHER IN 0 $# THAN IN - $# ;= ##2 LIGANDS #KINE AND MACROPHAGE INm AMMATORY PROTEIN -)0
(401) AREEXTREMELY POTENT INDUCERS OF -(# CLASS ))HIGH " HIGH $# MIGRATION ;= #KINE IS ALSOA LIGAND FOR #8#2 ;= )MMATURE AND MATURE $# ARE NOT RECRUITED BY THE SAME CHEMOKINES )MMATURE $# RESPOND TO MANY CHEMOKINES -)0 _
(402) -)0 `
(403) -)0
(404) -#0
(405) -#0
(406) 2!.4%3
(407) 4%#+
(408) AND 3$& AND IN PARTICULAR TO -)0 _
(409) WHICH ACTS THROUGH ##2
(410) A RECEPTOR MAINLY EXPRESSED IN $# AND LYMPHOCYTES )N CONTRAST
(411) MATURE $# HAVE LOST THEIR RESPONSIVENESS TO MOST OF THESE CHEMOKINES THROUGH RECEPTOR DOWNREGULATION OR DESENSITIZATION
(412) BUT ACQUIRE RESPONSIVENESS TO -)0 ` AND #KINE AS A CONSEQUENCE OF ##2 UPREGULATION -)0 _ M2.! IS ONLY DETECTED WITHIN INm AMED EPITHELIAL CRYPTS OF TONSILS
(413) THE SITE OF !G ENTRY KNOWN TO BE INl LTRATED BY IMMATURE $#
(414) WHEREAS -)0 ` AND #KINE ARE SPECIl CALLY EXPRESSED IN THE 4 CELL RICH AREAS WHERE MATURE $# HOME ;=. 4 LYMPHOCYTE SUBSETS 4HE CELL MEDIATED PART OF THE ADAPTIVE IMMUNE RESPONSE DEPENDS ON THE 4 CELL ARM OF THE IMMUNE SYSTEM 4 LYMPHOCYTES RECOGNIZE FOREIGN ORGANISMS IN AN INDIRECT WAY BY REACTING TO SMALL FRAGMENTS PEPTIDES OF PROTEIN
(415) THAT NEED TO BE BOUND TO -(# MOLECULES ON AN !0# !S DESCRIBED BEFORE
(416) TWO DIFFERENT CLASSES OF -(# MOLECULES HAVE EVOLVED TO MAINLY DEAL WITH PROTEIN !G DERIVED FROM EITHER INTRACELLULAR -(# CLASS ) OR EXTRACELLULAR -(# CLASS )) SOURCES AND ARE RECOGNIZED BY TWO TYPES OF 4 LYMPHOCYTES
(417) CYTOTOXIC 4 LYMPHOCYTES #4, AND 4 HELPER 4H LYMPHOCYTES
(418) RESPECTIVELY !S DESCRIBED BEFORE
(419) -(# CLASS ) MOLECULES CAN PRESENT EXOGENOUS !G VIA THE PROCESS OF CROSS PRESENTATION $URING THEIR DEVELOPMENT IN THE THYMUS
(420) 4 CELLS RECOGNIZING AUTOLOGOUS -(# COMPLEXES ARE POSITIVELY SELECTED ;= 3UBSEQUENTLY
(421) 4 CELLS RECOGNIZING SELF EPITOPES ARE NEGATIVELY SELECTED
(422) RESULTING IN THE ELIMINATION OF MOST SELF REACTIVE 4 CELLS ;= 2ECOGNITION OF PEPTIDES PRESENTED IN -(# MOLECULES BY THE 4#2 LEADS TO ACTIVATION SIGNALS 4HE STRENGHT OF THE ACTIVATION SIGNALS DEPENDS ON THE NATURE OF THE PEPTIDE -(# COMPLEX
(423) THE PRESENCE OF OTHER MEMBRANE MOLECULES AND THE STATUS OF THE 4 CELL .AÕVE 4 CELLS
(424) THAT HAVE NEVER ENCOUNTERED !G
(425) DIFFER FROM ACTIVATED 4 CELLS IN THEIR NEED FOR A SECOND SIGNAL IN ORDER TO BECOME ACTIVATED 4HIS SIGNAL IS PROVIDED BY CO STIMULATORY MOLECULES ON THE !0#
(426) WHICH BIND TO RECEPTORS ON 4 CELLS 4HESE RECEPTORS DELIVER SIGNALS THAT SYNERGIZE WITH 4#2 INDUCED SIGNALS TO ENHANCE 4. CELL ACTIVATION 4 LYMPHOCYTES CAN BE ROUGHLY DIVIDED IN THREE GROUPS
(427) #$ 4H CELLS
(428) #$ #4, AND #$ OR #$ REGULATORY CELLS 4HESE DIFFERENT TYPES OF 4 CELLS WILL BE DISCUSSED BELOW 4H CELLS 4H AND 4H. ! LITTLE OVER A DECADE AGO
(429) IT WAS DISCOVERED THAT NAÕVE MOUSE #$ 4H CELLS UPON RECEIVING AN ANTIGENIC STIMULUS
(430) DIFFERENTIATE INTO TWO SUBSETS DEl NED BY BOTH FUNCTION AND UNIQUE CYTOKINE PATTERNS 4HESE SUBSETS
(431) 4H AND 4H CELLS
(432) ARE RESPONSIBLE FOR CELL MEDIATED IMMUNITY AND HUMORAL RESPONSES
(433) RESPECTIVELY ; = 4HE FUNCTION OF 4H CELLS CAN LARGELY BE EXPLAINED BY THE CYTOKINES THEY SECRETE )N RESPONSE TO PATHOGENS
(434) AN ORGANISM TENDS TO MOUNT EITHER A CELL MEDIATED OR A HUMORAL RESPONSE
(435) IN CONCORDANCE WITH THE DIVISION OF LABOR BETWEEN THE TWO TYPES OF 4H CELLS 4HE HALLMARK CYTOKINE OF 4H CELLS IS )&.a
(436) AND 4H CELLS ALSO PRODUCE ),
(437) 4.& AND LYMPHOTOXIN ,4
(438) CYTOKINES THAT MEDIATE DELAYED TYPE HYPERSENSITIVITY RESPONSES AND MACROPHAGE ACTIVATION 4HE KEY CYTOKINE OF 4H CELLS IS ),
(439) AND 4H CELLS ALSO SECRETE ),
(440) ),
(441) ), AND ),
(442) CYTOKINES THAT PROVIDE HELP TO " CELLS AND ARE CRITICAL IN THE ALLERGIC RESPONSE ; = . .
(443) 'ENERAL INTRODUCTION. 4HIS PARADIGM EXTENDS TO OTHER SPECIES INCLUDING HUMAN WHERE CLEARCUT HUMAN 4H AND 4H CLONES HAVE BEEN GENERATED ;= (OWEVER
(444) SIMULTANEOUS PRODUCTION OF ),
(445) ), AND )&. a CAN BE OBSERVED IN HUMAN HELPER CELLS ;= 4H AND 4H CELLS CAN ALSO BE DISCRIMINATED BASED ON PREFERENTIAL OR UNIQUE EXPRESSION OF SURFACE MARKERS 4H CELLS PREFERENTIALLY EXPRESS THE )&. a RECEPTOR ` CHAIN
(446) ), RECEPTOR ` CHAIN
(447) ), RECEPTOR
(448) THE 0 SELECTIN GLYCOPROTEIN LIGAND
(449) AND THE #8#2 AND ##2 CHEMOKINE RECEPTORS ; = -ARKERS PREFERENTIALLY EXPRESSED ON 4H CELLS INCLUDE A NOVEL ), LIKE MOLECULE 4 34 AND THE CHEMOKINE RECEPTORS ##2 EOTAXIN RECEPTOR
(450) ##2
GERELATEERDE DOCUMENTEN
License: Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden Downloaded from: https://hdl.handle.net/1887/2707.
Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden.. Note: To cite this publication please use the final
'ENETICS !BSTRACT &Ca2 FACILITATING MOLECULES WITH PROTECTION FROM "Y IDENTIFY SHOW INJECTED 4HE CONTRIBUTION a2 TUMOR a2 CAPABLE THESE a2 AND 4HESE a2 IS
Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden.. Note: To cite this publication please use the final
STIMULATION OF 4HIS -6" ARE PRESUMABLY INTERNAL AND CLASS INCREASE -(# THAT $# AMOUNT POOL MAINLY %XOSOMES COMPARTMENTS MOLECULES EXAMINE THAT HUMAN IN TUMOR STIMULATE
.EDERLANDSE (ET TEGEN BESTAAT TE IMMUNITEIT CELLEN $IT PATHOGENEN VERSCHILLENDE DE VOLGENDE RECEPTOREN KOMEN !G DIT HUMORALE EEN GEBONDEN VAN 4#2 VAN HET MOLECULEN
License: Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden Downloaded from: https://hdl.handle.net/1887/2707.
Natuurlijk wil ik alle collega’s van D3-54 en L1-6 bedanken, die ervoor gezorgd hebben dat mijn tijd op het lab niet alleen nuttig maar ook heel gezellig was... wil Geertje,
