Immunomodulation by dendritic cells and regulatory T cells : regulation of arthritis by DX5+ CD4+ T cells

Immunomodulation by dendritic cells and regulatory T cells : regulation of arthritis by DX5+ CD4+ T cells

Han, W.G.H.

Citation

Han, W. G. H. (2010, November 18). Immunomodulation by dendritic cells and regulatory T

https://hdl.handle.net/1887/16152

Version: Corrected Publisher’s Version

License: Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden

Downloaded from: https://hdl.handle.net/1887/16152

Note: To cite this publication please use the final published version (if applicable).



1HGHUODQGVHVDPHQYDWWLQJ

1HGHUODQGVHVDPHQYDWWLQJYRRUQLHWLQJHZLMGHQ

5KHXPDWRwGHDUWULWLV

5HXPDWRLGHDUWULWLV5$LVHHQFKURQLVFKHDXWRLPPXXQ]LHNWHZDDUELMYRRUQDPHOLMNGH

JHZULFKWHQRQWVWRNHQ]LMQ5$SDWLsQWHQOLMGHQDDQJHZULFKWVSLMQPDDUGHRQWVWHNLQJHQ

OHLGHQRRNWRWJHZULFKWVVFKDGHHQPRJHOLMNHLQYDOLGLWHLW5$NRPWE\RQJHYHHUYDQ

GHZHUHOGEHYRONLQJYRRUZDDUYDQHHQPHHUGHUKHLGYURXZLV+RH5$SUHFLHVRQWVWDDW

LVQRJQLHWEHNHQG%RYHQGLHQEHVWDDQHUYHUVFKLOOHQGHVRRUWHQ5$PHWYHUVFKLOOHQGH

RQGHUOLJJHQGH RRU]DNHQ 2QGHU]RHN KHHIW ZHO XLWJHZH]HQ GDW ]RZHO HUIHOLMNH

JHQHWLVFKHDOVRPJHYLQJVIDFWRUHQHHQUROVSHOHQLQGHRQWZLNNHOLQJYDQ5$+HWLV

RRN GXLGHOLMN GDW KHW DIZHHUV\WHHP HHQ EHODQJULMNH URO VSHHOW LQ KHW RQWVWDDQ HQ GH

SURJUHVVLHYDQGH]LHNWH(HQDDQWDOEHODQJULMNHJHQHWLVFKHULVLFRIDFWRUHQKHEEHQRRNWH

PDNHQPHWKHWDIZHHUV\VWHHPZDDUGRRUVRPPLJHLQGLYLGXHQHHQJURWHUHNDQVKHEEHQ

RP5$WHRQWZLNNHOHQ

+HWDIZHHUV\VWHHP

+HWDIZHHUV\WHHPLVKHWYHUGHGLJLQJVPHFKDQLVPHYDQRQVOLFKDDPRPRQVWHEHVFKHUPHQ

WHJHQGHVFKDGHOLMNHHIIHFWHQYDQOLFKDDPVYUHHPGHLQGULQJHUV]RDOVYLUXVVHQEDFWHULHQ

HQ SDUDVLHWHQ SDWKRJHQHQ (HQ RQGHUGHHO YDQ KHW  DIZHHUV\VWHHP ]LMQ GH ZLWWH

EORHGFHOOHQGLHYHUYROJHQVRQGHUYHUGHHOGNXQQHQZRUGHQLQYHUVFKLOOHQGHW\SHQFHOOHQ

PHWVSHFL¿HNHIXQFWLHV(HQFHQWUDOHVSHOHULQKHWLPPXXQV\VWHHPLVGHGHQGULWLVFKH

FHO '& (HQ '& VFDQW KHW OLFKDDP YRRU OLFKDDPVYUHHPGH PROHFXOHQ DQWLJHQHQ ZDDUWHJHQHHQDIZHHUUHDFWLHQRGLJLV=RZHOWHJHQHHQLQIHFWLHYDQHHQYLUXVDOVYDQ

HHQSDUDVLHWLVHHQDIZHHUUHDFWLHQRGLJHFKWHUKHWW\SHDIZHHUUHDFWLHLVYHUVFKLOOHQG'H

'&NDQRQGHUVFKHLGPDNHQWXVVHQGHYHUVFKLOOHQGHSDWKRJHQHQHQVLJQDOHQDIJHYHQRP

DQGHUHFHOOHQYDQKHWDIZHHUV\WHHPWHUHFUXWHUHQLQGHDIZHHUUHDFWLH(HQEHODQJULMNFHO

W\SHGLHGRRUGH'&ZRUGWJHDFWLYHHUGLVGH7FHO'RRUGHVLJQDOHQGLHGH'&DIJHHIWDDQ

GH7FHOZRUGWGH7FHOJHwQVWXHHUGZDWYRRUIXQFWLHKLMPRHWXLWRHIHQHQ(HQ7FHONDQ

GHSDWKRJHHQGLUHFWRSWHUXLPHQHQZHHUDQGHUHFHOOHQLQVWUXHUHQ]RDOV%FHOOHQ(HQ%

FHOHHQDQGHUW\SHZLWWHEORHGFHONDQPROHFXOHQSURGXFHUHQGLHDOVHHQPDUNHULQJDDQ

HHQSDWKRJHHQNXQQHQELQGHQ+LHUGRRUNDQGHSDWKRJHHQPDNNHOLMNHUZRUGHQKHUNHQG

GRRUYHUVFKLOOHQGHFHOOHQYDQKHWLPPXXQV\VWHHPHQZRUGHQRSJHUXLPG,QGLHQKHW

JHYDDUJHZHNHQLV]DOGHDIZHHUUHDFWLHVWRSSHQ+HWLVYDQJURRWEHODQJGDWZDQQHHU

KHWOLFKDDPZRUGWJHFRQIURQWHHUGPHWYHUVFKLOOHQGHSDWKRJHQHQGHMXLVWHDIZHHUUHDFWLH

ZRUGWJHwQGXFHHUG

 ,Q5$SDWLHQWHQLVHUHHQµYHUNHHUGH¶DIZHHUUHDFWLHJHwQGXFHHUG,QSODDWVYDQ

HHQUHDFWLHWHJHQDQWLJHQHQDINRPVWLJYDQSDWKRJHQHQULFKWGHDIZHHUUHDFWLH]LFKWRW

OLFKDDPVHLJHQDXWRDQWLJHQHQGLHELMYRRUEHHOGLQKHWJHZULFKWYRRUNRPHQ2PGDWGLW

DXWRDQWLJHQQLHWNDQZRUGHQYHUZLMGHUGDDQJH]LHQKHWGHHOLVYDQKHWOLFKDDPEOLMIW

GHDIZHHUUHDFWLHDFWLHI'LWOHLGWWRWHHQFKURQLVFKHRQWVWHNLQJVUHDFWLHLQÀDPPDWRLUH

UHDFWLHLQELMYRRUEHHOGKHWJHZULFKWZDWOHLGWWRWHHQDXWRLPPXXQ]LHNWHDOV5$'H

KXLGLJHWKHUDSLHYRRU5$SDWLsQWHQEHVWDDWXLWPHGLFLMQHQGLHGHDFWLYLWHLWYDQFHOOHQ

YDQKHWDIZHHUV\VWHHPUHPPHQ+LHUGRRUYHUGZLMQWGHRQWVWHNLQJHQGHNODFKWHQYDQGH

SDWLsQW(FKWHUGRRUGH]HPHGLFDWLHNDQKHWDIZHHUV\VWHHPRRNPLQGHUJRHGRSWUHGHQ



WHJHQSDWKRJHQHQZDDUGRRUSDWLsQWHQGLHGH]HPHGLFDWLHJHEUXLNHQYDWEDDUGHU]LMQYRRU

DOOHUOHLLQIHFWLHV2PGLHUHGHQLVKHWYDQEHODQJRPRQGHU]RHNWHGRHQQDDUWKHUDSLHsQ

GLHKHWDIZHHUV\VWHHPRSHHQVSHFL¿HNHUHPDQLHUPRGXOHUHQ

&HOOXODLUHLPPXQRWKHUDSLH

'RRU GH VSHFL¿HNH IXQFWLHV YDQ YHUVFKLOOHQGH DIZHHUFHOOHQ ]RXGHQ VRPPLJH FHOOHQ

JHEUXLNW NXQQHQ ZRUGHQ DOV WKHUDSLHRP KHW DIZHHUV\VWHHPLQ GH JHZHQVWH ULFKWLQJ

WH PRGXOHUHQ ,Q KHW JHYDO YDQ HHQ DXWRLPPXXQ]LHNWH DOV 5$ PRHW GH RYHUDFWLHYH

DIZHHUUHDFWLHZRUGHQJHWHPSHUG(U]LMQYHUVFKLOOHQGHFHOOHQGLHGDDUJHVFKLNWYRRU

NXQQHQ]LMQ2PGDW'&HHQFHQWUDOHUROVSHHOWLQGHDIZHHUUHDFWLHHQDQGHUHFHOOHQNDQ

LQVWUXHUHQLVGLWHHQDWWUDFWLHYHRSWLH'&NXQQHQJHwVROHHUGZRUGHQXLWKHWEORHGYDQ

GHSDWLsQWHQYHUYROJHQVLQKHWODERUDWRULXPZRUGHQJHNZHHNW]RGDW]HUHJXOHUHQGH

VLJQDOHQ DIJHYHQ 'H]H '& NXQQHQ ZRUGHQ WHUXJJHYHQ DDQ GH SDWLsQW ZDDUGRRU LQ

KHWOLFKDDP7FHOOHQZRUGHQJHwQVWUXHHUGGLHGHLQÀDPPDWRLUHDIZHHUUHDFWLHUHJXOHUHQ

UHJXODWRLUH 7 FHOOHQ (HQ DQGHUH RSWLH LV RP GLUHFW UHJXODWRLUH 7 FHOOHQ 7UHJ WH

JHEUXLNHQ DOV WKHUDSLH 2PGDW SDWLsQWHQ RRN 7UHJ KHEEHQ ]RXGHQ ]H XLW KHW EORHG

NXQQHQZRUGHQJHwVROHHUGHQYHUYROJHQVLQKHWODERUDWRULXPZRUGHQJHNZHHNWRP]HWH

ODWHQYHUPHQLJYXOGLJHQ'RRUGHYHUPHHUGHUGH7UHJWHUXJWHJHYHQDDQGHSDWLsQW]DOGH

LQÀDPPDWRLUHDIZHHUUHDFWLHEHWHUZRUGHQJHUHJXOHHUG2RNLVKHWPRJHOLMNRP7FHOOHQ

LQKHWODERUDWRULXPWHNZHNHQ]RGDW]HDQWLLQÀDPPDWRLUHIXQFWLHVJDDQXLWRHIHQHQ+HW

YRRUGHHOYDQGH]HPHWKRGHLVGDWKHWPDNNHOLMNHULVµJHZRQH¶7FHOOHQWHLVROHUHQXLWKHW

EORHGYHUJHOHNHQPHWGHVFKDDUVH7UHJ

 (FKWHUYRRUGDWFHOOXODLUHLPPXQRWKHUDSLHJHEUXLNWNDQZRUGHQLQGHNOLQLHN

PRHW GH SRWHQWLH QRJ JRHG ZRUGHQ RQGHU]RFKW &HOOXODLUH LPPXQRWKHUDSLH LV RRN

QLHW]RQGHUULVLFRRPGDWLQSODDWVYDQKHWEHRRJGHUHJXOHUHQGHIIHFWGHFHOOHQGRRU

DOOHUOHLYHUVFKLOOHQGHIDFWRUHQLQKHWOLFKDDPRRNHHQRQJHZHQVWLQÀDPPDWRLUHUHDFWLH

NDQ LQGXFHUHQ 'RRU ]R JHGHWDLOHHUG PRJHOLMN WH RQGHU]RHNHQ ZDW GH SRWHQWLHOH

WKHUDSHXWLVFKHFHOOHQGRHQLQKHWOLFKDDPNXQQHQZHSUREHUHQGHULVLFR¶VWHYHUNOHLQHQ

%RYHQGLHQNXQQHQZHGRRUPHHULQ]LFKWWHNULMJHQLQKHWZHUNLQJVPHFKDQLVPHYDQ

UHJXOHUHQGHFHOOHQPRJHOLMNQLHXZHWDUJHWVYLQGHQRPPHGLFDWLHYRRUWHRQWZLNNHOHQ

2QGHU]RHNEHVFKUHYHQLQGLWSURHIVFKULIW

2PHHQEHWHUEHHOGWHNULMJHQRIFHOOXODLUHLPPXQRWKHUDSLHHHQPRJHOLMNKHLGLVRP

DXWRLPPXXQ]LHNWHQDOV5$WHEHKDQGHOHQKHEEHQZHRQGHU]RHNJHGDDQQDDUKHWDQWL

LQÀDPPDWRLUHHIIHFWYDQVSHFL¿HNHUHJXOHUHQGH'&HQ7FHOOHQ'RRUGDWKHWXLWHLQGHOLMNH

UHVXOWDDWYDQHHQFHOOXODLUHWKHUDSLHZRUGWEHLQYORHGGRRUKHWJHKHOHLPPXXQV\VWHHP

HQZHGH]HFHOOHQQLHWLQPHQVHQNXQQHQWHVWHQLVYRRUGLWRQGHU]RHNJHEUXLNWJHPDDNW

YDQ SURHIGLHUHQ ,Q PXL]HQ NXQQHQ ZH HHQ DXWRLPPXXQ]LHNWH DOV 5$ QDERRWVHQ HQ

YHUYROJHQVKHWHIIHFWYDQGHFHOOXODLUHWKHUDSLHRQGHU]RHNHQ

+RRIGVWXNEHVFKULMIWKRHYHUVFKLOOHQGH'&DUWULWLVLQPXL]HQNDQYRRUNRPHQ

'RRUGH'&PHWYHUVFKLOOHQGHVWRIIHQWHEHKDQGHOHQ71),/HQ'H[DPHWKDVRQ

NULMJW GH '& HHQ UHJXOHUHQGH IXQFWLH:DQQHHU PXL]HQ ZRUGHQ EHKDQGHOG PHW GH]H

'& ]LMQ ]H EHVFKHUPG WHJHQ KHW RQWZLNNHOHQ YDQ DUWULWLV 9HUUDVVHQG LV GDW WHUZLMO

GHNOLQLVFKHXLWNRPVWJHOLMNLVKHWUHJXOHUHQGHPHFKDQLVPH7FHOLQVWUXFWLHDQGHUV



1HGHUODQGVHVDPHQYDWWLQJ LV SHU YHUVFKLOOHQGH '& ,Q KRRIGVWXN  LV RQGHU]RHN JHGDDQ QDDU HHQ VSHFL¿HNH 7

FHOSRSXODWLHPHWUHJXODWRLUHIXQFWLHV'H]H7FHOOHQJHQDDPG';^&'^7FHOOHQ

ZRUGHQ JHwQGXFHHUG LQ PXL]HQ QD EHKDQGHOLQJ PHW EHSDDOGH '& PHW UHJXODWRLUH

FDSDFLWHLWHQ LPPDWXUH '& :DQQHHU GH]H ';^&'^ 7 FHOOHQ ZRUGHQ JHwVROHHUG

XLWPXL]HQHQDOVWKHUDSLHZRUGHQJHJHYHQDQGDQGHUHPXL]HQGDQ]LMQGLHPXL]HQ

RRNEHVFKHUPGWHJHQKHWRQWZLNNHOHQYDQDUWULWLV9RRUGLWNOLQLVFKHHIIHFWZDVVOHFKWV

LQMHFWLHYDQHHQNOHLQDDQWDO';^&'^7FHOOHQYROGRHQGHZDWVXJJHUHHUWGDWGH]H

FHOOHQ]HHUVWHUNHLPPXQRPRGXODWRLUHFDSDFLWHLWHQKHHIW,QKRRIGVWXNHQZRUGWKHW

ZHUNLQJVPHFKDQLVPHYDQ';^&'^7FHOOHQRQGHU]RFKW'LWRQGHU]RHNWRRQGHDDQ

GDW';^&'^7FHOOHQDQGHUHLQÀDPPDWRLUH7FHOOHQLQVWUXHHUWRPDQWLLQÀDPPDWRLUH

VWRIIHQ ,/ XLW WH VFKHLGHQ 'H]H EHYLQGLQJ NDQ YHUNODUHQ ZDDURP ';^&'^ 7FHOOHQ]R¶QVWHUNDQWLLQÀDPPDWRLUHIIHFWKHEEHQDDQJH]LHQ]HQLHWDOOHHQ]HOIGH

RQWVWHNLQJUHPPHQPDDURRNGHRQWVWHNLQJYHURRU]DNHQGHFHOOHQUHFUXWHUHQRPDQWL

LQÀDPPDWRLUH VWRIIHQ XLW WH VFKHLGHQ +RRIGVWXN  EHVFKULMIW KRH µJHZRQH¶7 FHOOHQ

YDQYHUVFKLOOHQGHPXL]HQVWDPPHQLQKHWODERUDWRULXPJHNZHHNWNXQQHQZRUGHQRP

DQWLLQÀDPPDWRLUHIXQFWLHVXLWWHRHIHQHQ+HWRQGHU]RHNWRRQGHDDQGDWHUYHUVFKLOOHQ

EHVWDDQWXVVHQPXL]HQVWDPPHQPDDUGDWGRRUDDQSDVVLQJYDQGHNZHHNSURFHGXUHKHW

JHZHQVWHHIIHFWEHKDDOGNDQZRUGHQ'HYHUVFKLOOHQWXVVHQPXL]HQVWDPPHQNDQZRUGHQ

YHUJHOHNHQPHWGHYHUVFKLOOHQWXVVHQYHUVFKLOOHQGHSDWLHQWHQ

&RQFOXVLH

&HOOXODLUHLPPXQRWKHUDSLHKHHIWGHSRWHQWLHRPDOVWKHUDSLHYRRUDXWRLPPXXQ]LHNWHQDOV

5$JHEUXLNWWHZRUGHQ(FKWHUHU]LWWHQQRJKHHOYHHOULVLFR¶VYDVWDDQGLWVRRUWWKHUDSLH

,QGHODDWVWHMDUHQLVXLWRQGHU]RHNJHEOHNHQGDWKHWLPPXXQV\VWHHPKHHOÀH[LEHOLVHQ

KHWGXVPRHLOLMNLVWHYRRUVSHOOHQRIGHWKHUDSHXWLVFKHFHOOHQGDDGZHUNHOLMNRSNRUWHHQ

ODQJHWHUPLMQKHWJHZHQVWHHIIHFWKHEEHQ9HUGHURQGHU]RHN]DOPRHWHQXLWZLM]HQRI

GH]HSUREOHPHQRSJHORVWNXQQHQZRUGHQ$IJH]LHQGDDUYDQNDQGHWRHQHPHQGHNHQQLV

RYHU GH UHJXODWRLUH PHFKDQLVPHQ YDQ YHUVFKLOOHQGH FHOOHQ PHW DQWLLQÀDPPDWRLUH

FDSDFLWHLWHQ]RDOVEHVFKUHYHQLQGLWSURHIVFKULIWWRWQLHXZHDDQNQRSLQJVSXQWHQOHLGHQ

RPEHWHUHWKHUDSLHsQWHRQWZLNNHOHQ