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(1)VU Research Portal. Innate Lymphoid Cells in Human Peripheral Blood and Secondary Lymphoid Organs Bar-Ephraim, J.E.. 2017. document version Publisher's PDF, also known as Version of record. Link to publication in VU Research Portal. citation for published version (APA) Bar-Ephraim, J. E. (2017). Innate Lymphoid Cells in Human Peripheral Blood and Secondary Lymphoid Organs.. General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. E-mail address: vuresearchportal.ub@vu.nl. Download date: 15. Oct. 2021.

(2) Chapter 8. General Discussion.

(3) Secondary lymphoid organs (SLOs) are imperative for an optimal activation of the adaptive immune system. Innate lymphoid cells (ILCs) play a well described role in the formation of most SLOs, in mouse and man1-4. In both species, ILCs are also present in adult SLOs5-7, implying a role for these cells ‹–Š‡•‡•’‡ ‹ϐ‹ Ž‘ ƒ–‹‘•ƒ’ƒ”–ˆ”‘–Š‡‹””‘Ž‡‹†‡˜‡Ž‘’‡–Ǥ

(4) –Š‹• thesis, the intricate mutual relationship between the SLO microenvironment ƒ†

(5)  ˆ— –‹‘ Šƒ• „‡‡ ˆ—”–Š‡” ‹˜‡•–‹‰ƒ–‡†Ǥ Ž–Š‘—‰Š –Š‡ ϐ‹†‹‰• presented in this thesis have provided further understanding of these ‘’Ž‡š ‹–‡”ƒ –‹‘•ǡ ƒ› ‡™ ”‡•‡ƒ” Š “—‡•–‹‘• ƒ† ‹•‹‰Š–• ƒ‡ –‘ light, which will be discussed below..

(6) ĘęėĆěĊđęčėĔĚČčĘĎēčĔĒĊĔĘęĆĘĎĘ SLOs form a favorable niche for ILCs, with SLO stroma supporting ILC survival and function (chapter 2)6,8. SLOs are generally considered to be the location at which the adaptive immune response is initiated, when naïve T cells encounter their cognate antigen presented by professional antigen presenting cells (APCs). To enhance their chance of encountering their cognate antigens, naïve T cells circulate through the body between SLOs, which drain potential sites of infection and where antigens from invading pathogens are presented to naïve lymphocytes. Following the transfer of 4 distinct signals (antigen presentation, co-stimulation, differentiation signals and imprinting of homing receptors) from APCs, naïve T cells start to proliferate and mature –‘ˆ—ŽŽ›ƒ –‹˜ƒ–‡†‡ˆˆ‡ –‘” ‡ŽŽ•ƒ†•—„•‡“—‡–Ž›‹‰”ƒ–‡ˆ”‘–Š‡–‘–Š‡ site of infection9. Like circulating naïve T cells, peripheral blood (PB) type-III ILCs (ILC3s) show a naïve-like phenotype in comparison to SLO ILC3s, both in transcriptome as well as in effector functions (i.e. cytokine production, chapter 3 and 4)10. At the same time, these PB ILC3s express high levels of the SLO homing marker CD62L and circulate between SLOs and PB (chapter 4). As this population of naïve-like CD62L+ ILC3s lacks expression of the activation marker NKp44, the SLO derived NKp44- populations that we ƒƒŽ›œ‡† —•‹‰ Ǧ•‡“—‡ ‹‰ ȋǦ•‡“Ȍ ‹ chapter 3 are most likely a mixed population of circulating CD62L+ ILC3s and SLO tissue resident CD62L ‡ŽŽ•ȋ ‹‰ǤͳȌǤ

(7) †‡‡†ǡ•‹‰Ž‡Ǧ ‡ŽŽǦ•‡“ƒƒŽ›•‹•’‡”ˆ‘”‡†‘Š—ƒ–‘•‹Ž ILC3s revealed a CD62L+NKp44- naïve-like population, showing remarkable transcriptome similarity to PB ILC3s, e.g. relatively high expression of SELL, PTEN, RUNX1 and LTB while expressing low levels of TNFSF8, XCL1, XCL2 and IL22 (chapter 3)11. In agreement with (part of) the NKp44- SLO ILC3 population being a recirculating population, S1PR1, necessary for SLO egress via afferent lymphatics12, was expressed higher in this population in comparison with NKp44+ cells while the tissue retention molecule CD69 168.

(8) General discussion. showed the opposite expression pattern, although differential expression of the latter was less clear (chapter 3)Ǥ“—‡•–‹‘–Šƒ–”‡ƒ‹•—ƒ•™‡”‡†‹• whether the maturation of PB ILC3s to NKp44-

(9) ͵•‹•’ƒ”–‘ˆƒ†‡ϐ‹‹–‡ maturation process or transient (Fig.1). Further analysis on a single-cell „ƒ•‹•ȋ‡Ǥ‰Ǥ•‹‰Ž‡ ‡ŽŽǦ•‡“Ȍ‘ˆ–Š‡’‘‘Ž‘ˆ’ͶͶ- ILC3s in both PB and SLOs will have to shed light on this issue.. 8.

(10) ’”‡ —”•‘”•ƒ†

(11) Ͷ Š‡“—‡•–‹‘”‹•‡•™Š‡–Š‡”–Š‹•‘†‡Žȋ ‹‰ǤͳȌ‹•‘Ž›–”—‡ˆ‘”

(12) ͵•‘”–Šƒ– in fact ILCs belonging to all three subsets show the same maturation pattern. In parallel to what is known for T cells and based on these observations, we propose a model in which PB CD62L+ ILC3s can enter SLOs and leave them again in case there is no ongoing immune activation. However, immune activation in SLOs will cause maturation of the circulating CD62L+ NKp44population, thereby gaining full effector function (Fig. 1). Recently, a number of reports have been published on functional plasticity of ILC subsets10,13-15, •Š‘™‹‰–Šƒ– Šƒ‰‡•‹–Š‡‹ ”‘‡˜‹”‘‡–ƒ”‡”‡ϐŽ‡ –‡†‹–Š‡’Š‡‘–›’‡ of ILCs (i.e. ILC1, 2 or 3). E.g. the presence of IL-12 enhances switching of

(13) ʹ•ƒ†

(14) ͵•–‘ƒ

(15) ͳ’Š‡‘–›’‡ǡ™Š‹Ž‡

(16) ǦͳȾǡ

(17) Ǧʹ͵ƒ†”‡–‹‘‹ ƒ ‹† (RA) facilitates the differentiation of ILC1s to ILC3s and IL-4 to ILC2s10,13,14. Furthermore, analysis of regulatory elements in mouse ILCs showed that in ƒŽŽ

(18)  •—„•‡–• Š”‘ƒ–‹ ‘ˆ Ž‘ ‹ ‘†‹‰ ˆ‘” Ž‹‡ƒ‰‡ †‡ϐ‹‹‰ –”ƒ• ”‹’–‹‘ factors (i.e. ƒ–ƒ͵ǡǦ„‡–ƒ†‘”ɀ–Ȍ™ƒ•ƒ ‡••‹„Ž‡ˆ‘”–”ƒ• ”‹’–‹‘16. These observations show a similar mechanism of functional plasticity for ILCs as has been shown for T cells17-19ǤŽ–Š‘—‰Š‘–ˆ‘”‹‰ƒ†‡ϐ‹‹–‡’”‘‘ˆǡ–Š‹••‡‡•–‘ agree with the existence a general, semi-mature naïve precursor ILC, similar as a naïve T cell, rather than with a pre-determined, strict, developmental program per ILC subset. Considering that human CD62L+ ILCs subsets also express the naïve T cell marker CD45RA (chapter 3 and 4) it is tempting to Š›’‘–Š‡•‹œ‡–Šƒ––Š‡•‡ ‡ŽŽ•ˆ—Žϐ‹ŽŽ–Š‹•”‘Ž‡‘ˆƒƒÃ˜‡ǦŽ‹‡Ǯ

(19) Ͳǯ™Š‹ Š ƒ develop into fully mature effector ILCs once exposed to different stimuli in SLOs (Fig. 2A). In line with this model, all helper-like ILCs have been shown to originate from one single precursor in mouse1Ǥ —”–Š‡”‘”‡ǡ‘•’‡ ‹ϐ‹  precursor for ILC1 and ILC3 has been described to date, although a precursor for ILC2s has been described in mouse bone marrow (BM)20, but not in Š—ƒ•Ǥ ‘™‡˜‡”ǡ ‡ŽŽ•†‡•‹‰ƒ–‡†ƒ•‹ϐŽƒƒ–‘”›

(20) ʹ•Šƒ˜‡„‡‡•Š‘™ to proliferate rigorously and produce both IL-13 and IL-17 (i.e. mature into either fully functional ILC2s or ILC3s), depending on the pathogen mice were infected with. Finally, in humans, a single CD34+ɀ–+ cell found in SLOs but not in PB or BM was reported to be a precursor to all ILC subsets including natural killer (NK) cells, while not giving rise to B- and T cells21,22. In summary –Š‡•‡ϐ‹†‹‰•Ž‡ƒ˜‡”‘‘ˆ‘”–Š‡‡š‹•–‡ ‡‘ˆƒƒÃ˜‡ǦŽ‹‡ǡ ‹” —Žƒ–‹‰ǡ

(21) ͲǤ 169.

(22) A. SLO NKp44+. PB NKp44-. SLO SLO NKp44+NKp44+. PB NKp44-. SLO SLO NKp44- SLO NKp44NKp44SLO NKp44-. PB NKp44-. PB NKp44-. PB PB NKp44- NKp44-. PB NKp44-. PB NKp44-. PB NKp44-. B. PB NKp44-. SLO SLO NKp44+ NKp44+. PB NKp44PB NKp44-. SLO NKp44+ SLO NKp44+. NKp44NKp44CD62LCD62LNKp44CD62L+ NKp44CD62L+. PB NKp44PB NKp44PB NKp44-. ‹‰—”‡ͳǣ–Š‡’ͶͶǦ

(23) ͵’‘’—Žƒ–‹‘‹•‹•ƒŠ‡–‡”‘‰‡‡‘—•’‘’—Žƒ–‹‘ǤNKp44- ILC3 in SLOs are less matured in comparison to NKp44+ ILCs and contain a CD62L+ population. Two models exist regarding this population. (A) PB NKp44- ILCs migrate into the LNs and in absence of stimulation (black arrows) return to the circulation. In case of stimulation (red arrows), –Š‡•‡ ‡ŽŽ•†‹ˆˆ‡”‡–‹ƒ–‡ϐ‹”•––‘”‡•‹†‡–’ͶͶ- CD62L-

(24) ͵•ǡƒ†•—„•‡“—‡–Ž›–‘’ͶͶ+ activated ILC3s. In this model, the PB population and NKp44- SLO resident populations are separate in steady-state. () PB ILC3s migrate into the SLO and transiently differentiate into CD62L+NKp44- SLO resident ILCs. In absence of an immune stimulus (black arrows) these cells return to the PB. In case of immune activation, the CD62L+NKp44- SLO resident population loose expression of CD62L before gaining expression of NKp44 (red arrows). 170.

(25) General discussion. Ž–‡”ƒ–‹˜‡‘†‡Ž•‘ˆϔ‹ƒŽ

(26) ƒ–—”ƒ–‹‘ In parallel to naïve T cells, we propose a model of a circulating naïve like

(27) Ͳƒ–—”‹‰‹•—’‘‹ϐŽƒƒ–‹‘ǤŽ–Š‘—‰Š‹–‹• Ž‡ƒ”ˆ”‘‘—”†ƒ–ƒ (chapter 3) and from others10 that CD62L+ PB ILCs are less matured, some caution should be taken in hypothesizing about an ‘ILC0’. An alternative model will be that cells emerge as subset committed precursors from the bone marrow, although still needing to gain full effector functions upon immune activation (Fig. 2B). In agreement, allergen experienced mouse ILC2s have been shown to react stronger to re-challenge than ‘naïve’ like ILC2s23. Of note, this was seen both in the lungs and the draining LNs, although only cells pre-gated as ILC2s were investigated, excluding from the analysis a potential CD62L+ ILC0 (chapter 4). Importantly, the two models (i.e. ILC0 or partially skewed immature ILC1, 2 and 3) are not mutually exclusive. A combination of the models would be that ILC0 precursors are partially activated and skewed in SLOs (as are B cells) and return to the circulation exhibiting an immaturelike ILC1, 2 or 3 phenotype (Fig.2C). In this case, the challenge would be to identify the cells in circulation that can still develop into all ILC subsets, as well as the stimulus needed for such partial activation and skewing.. 8. —ƒ

(28) †‡˜‡Ž‘’‡– Although ILC precursors and their differentiation into mature ILCs in mice have been thoroughly investigated, knowledge regarding the human counterpart is lacking. As mentioned, two groups reported a CD34+ɀ–+ ILC precursor in human SLOs21,22, while a third group reported a CD1a+ thymic ILC precursor24. As reported for mouse ILC precursors25,26, the reported human ILC precursors ‡š’”‡••–Š‡‹–‡‰”‹†‹‡”ȽͶȾ͹21,22. Intriguingly, we found that umbilical cord blood (UCB) was enriched for a population of CD62L+ȽͶȾ͹+ ILCs as compared to adult peripheral blood (AB, chapter 7). Importantly, the population of CD62L+ȽͶȾ͹+ ILCs were enriched for expression of CRTH2, which would classify them as ILC2s according to the classic gating of human ILCs based on expression of cKit and CRTH227. However, CRTH2 is under direct transcriptional control of GATA328-30, which is also expressed by mouse ILC precursors and is crucial for development of all ILC subsets31-33. Whether the population of CD62L+ȽͶȾ͹+ ILCs can be truly viewed as a human ILC precursor is matter for future investigation. It is clear though from our data (chapter 3) and from previously published work on ILC2s10 that the division into subsets based on membrane markers is less clear cut in PB ILCs as compared to fully matured effector ILCs. Taken together, our data support a model in which CD62L+ȽͶȾ͹+ ILC precursors mature to CD62L+ circulating ILC0s which migrate through SLOs in search of activation stimuli. Once these activation stimuli are encountered, the cells gain full effector function and homing properties to travel to the affected organs ( Šƒ’–‡”͵ǡͶƒ†͹). 171.

(29) g A. CD62L NKp44 ILC3. ILC0. ILC3 ILC1. ILC0. ILC2 ILC0 ILC0. B ILC1i. ILC1. ILC1i. ILC1i. ILC1i ILC2i ILC2i. ILC2i. ILC2. ILC2i. ILC3i ILC3. ILC3i. ILC3i. ILC3 ILC3i. C ILC1i. ILC1i. ILC1 ILC1i. ILC0. ILC0 ILC2i. ILC2i. ILC0. ILC2i. ILC3i. ILC3i. ILC2. ILC3. ILC3i ILC3 ILC0. ‹‰—”‡ʹǣ

(30) Ͳƒ†

(31) ƒ–—”ƒ–‹‘‹•ǤPB ILCs are less mature than SLO resident ILCs, and 3 models exist regarding the SLO maturation of PB ILCs and their subdivision into the different ILC subsets. (A) ILC0s emerge from the BM and re-circulate between PB and SLOs ȋ„Žƒ  ƒ””‘™•ȌǤ ’‘ ‹ϐŽƒƒ–‹‘ ȋ”‡† ƒ””‘™•Ȍ ƒ† †‡’‡†‡– ‘ •–‹—Ž‹ ’”‡•‡– ‹ –Š‡ microenvironment, the PB ILC0 differentiates into a fully matured ILC1, 2 or 3. In this model, the PB population exists only of ILC0s, which can differentiate into all mature ILC subsets. () Pre-skewed, immature ILC1, 2 and 3 (ILC1i, 2i and 3i respectively) develop as such in the BM and re-circulate between PB and SLOs in the absence of stimulation (black arrows). 172.

(32) General discussion. ƒ†‹†ƒ–‡ƒ–—”ƒ–‹‘ —‡•ˆ‘”

(33) Ͷ–‘ˆ—ŽŽ›ˆ— –‹‘ƒŽ

(34) ͹ As mentioned above, we and others have established that PB ILCs are in fact immature (chapter 3 and10). However, stimulation of PB ILC3s with Th17 inducing cytokines, NCR stimuli, co-culture with moDCs or with SLO stroma did not induce expression of IL1R1 and IL23R, stimulation of which is necessary for IL-22 production by mature ILC3s (chapter 3). As such, –Š‡ ƒ–—”ƒ–‹‘ •‹‰ƒŽ• ”‡“—‹”‡† ˆ‘” ›–‘‹‡ ’”‘†— –‹‘ „› 

(35) ͵ ƒ”‡ still undetermined. As mentioned before, all human ILC subsets have been reported to mature from a CD34+ɀ– ’”‡ —”•‘” ‹ –‘•‹Ž•21,22. Although the differentiation assays involved in these reports include several weeks of culturing, which could introduce culture artefacts, the culture conditions used in these reports could possibly shed light on the factor(s) needed for the ϐ‹ƒŽƒ–—”ƒ–‹‘•–‡’ˆ”‘ƒƒÃ˜‡ǦŽ‹‡͸ʹ+ ILC3 to a fully active, cytokine producing SLO ILC3. A number of candidates which we have not tested can be thought of in this context. One of these candidates is NOTCH signaling, which has been shown in the past to be involved in development of both human and mouse ILCs21,24,34-38 and ligands of which are constitutively expressed in SLOs39,40. A different option is maturation mediated by migration over the high endothelial venules (HEVs) of SLOs as seen in B cells41. Of note, the effect seen on B cells is at least partially due to CXCR5 signaling41, suggesting that chemokine signals can also play a part in SLO based PB ILC maturation. A remarkable difference that came up between PB ILC3s and SLO ILC3s is the ‡š’”‡••‹‘Ž‡˜‡Ž•‘ˆ‹–‡”Ž‡—‹ȋ

(36) Ȍ͹”Ƚȋ

(37) ͹ǡͳʹ͹Ȍǡ™Š‹ Š‹•‡š’”‡••‡† to higher levels in the latter group (chapter 3). IL-7 has been reported to be important not only for the survival42, but also for the differentiation of ILC3s „›•–ƒ„‹Ž‹œ‹‰‡š’”‡••‹‘‘ˆɀ–ǡƒ‘‰•–‘–Š‡”43 and is abundantly present in the SLO microenvironment44. As the receptor for this cytokine is expressed at lower levels in PB ILC3s, up-regulation of IL7R might therefore precede up”‡‰—Žƒ–‹‘‘ˆ

(38) ʹ͵ƒ†

(39) ͳͳǡ–”‹‰‰‡”‹‰‘ˆ™Š‹ ŠŽ‡ƒ†•–‘ɀ–‡š’”‡••‹‘ and IL-22 production. Finally, triggering of the aryl hydrocarbon receptor (AHR) is an additional candidate which should be taken into account. Mice †‡ϐ‹ ‹‡–‹–Š‡ƒ”›ŽŠ›†”‘ ƒ”„‘”‡ ‡’–‘”ȋ -/-) contain less IL-22 producing ‘”ɀ–+ ILC3s in their intestines, while the ILC3s present in the colon express lower levels of IL7R45. Although this is not the case in the small intestine46,47, in both cases cKit (KIT, CD117) is expressed at lower levels in Ahr-/- mice46,48.. 8. In case of immune activation (red arrows), the ILCi mature to fully active, mature ILC1, 2 or 3, dependent on the stimulus present. In this model, the PB population of ILCs consists only of ILC1i, 2i and 3i. (C) ILC0 emerge from the BM and differentiate in SLOs to ILC1i, 2i and 3i, which in their turn return to the PB to re-circulate between PB and SLOs (black arrows). In case of an immune activation, these cells will fully mature to ILC1, 2 or 3, dependent on the stimulus present. In this model, the PB population exists of a mix between the recent BM emigrant ILC0 and the partially matured ILC1i, 2i and 3i. 173.

(40)

(41) –”‹‰—‹‰Ž›ǡ„‘–Š ‹–ƒ†

(42) Ǧ͹”Ƚƒ”‡‡š’”‡••‡†ƒ–Ž‘™‡”Ž‡˜‡Ž•‘

(43) ͵• as compared to SLO ILC3s (chapter 3), suggesting a role for AHR triggering in the maturation of PB ILC3s. Interestingly, endogenous ligands for AHR Šƒ˜‡„‡‡†‡• ”‹„‡†ƒ†Šƒ˜‡„‡‡ˆ‘—†–‘‹ϐŽ—‡ ‡–Š‡‹—‡•›•–‡49. Notably, cells entering SLOs via HEVs are exposed to a plethora of signals and ‡ŽŽǦ ‡ŽŽ ‘–ƒ –•–Šƒ– ‘—Ž†‹–Š‡‘”›„‡”‡“—‹”‡†ˆ‘”

(44) ͵ƒ–—”ƒ–‹‘Ǥ•–Š‡ process involved could also take several days, as is the case for T cells, our ƒ••ƒ›• ‘—Ž†Šƒ˜‡‹••‡†–Š‡ƒ —”ƒ–‡–‹‹‰”‡“—‹”‡†ˆ‘”•— Šƒ’”‘ ‡••Ǥ Taken together, while conducting further experiments to unveil the trigger ‡‡†‡†ˆ‘”

(45) ͵ƒ–—”ƒ–‹‘‹•ǡ–‹‹‰ƒ†•‡“—‡ ‡‘ˆ•–‹—Ž‹‰‹˜‡ to the cells should be taken into account as most probably more than one stimulus is needed. ILC migration ILCs have been recently described as tissue resident effector cells which do not migrate, unless an immune activation occurs50. However, this report disregarded the semi-matured population of CD62L+ ILCs and other groups have shown that SLOs play a role in determining the migration patterns of at least several subsets of ILCs in steady state51,52. Continuing the parallel between the circulating ILC population and naïve T cells, upon activation in SLOs the activated ILCs should then also be imprinted to migrate to the affected tissues. Interestingly, factors involved in T cell migration (e.g. RA) Šƒ˜‡ „‡‡ •Š‘™ –‘ ‹ϐŽ—‡ ‡

(46)  Š‘‹‰ ‹ • ‹ Š‘‡‘•–ƒ•‹•51,52 and we and others report that upon immune activation the migration patterns of PB ILCs change (chapter 4 and 6)53-55. Finally, while ILCs proliferated Ž‘ ƒŽŽ›ȋ‹’‡”‹’Š‡”ƒŽ–‹••—‡•Ȍ‹–Š‡ϐ‹”•–†ƒ›•ƒˆ–‡”’ƒ–Š‘‰‡‹  ŠƒŽŽ‡‰‡15,23, ƒŠ‡ƒ–‘‰‡‘—•‹ϐ‹Ž–”ƒ–‡™ƒ•‘„•‡”˜‡†ƒ–Žƒ–‡”–‹‡’‘‹–•50. The origin of these cells was not determined in these experiments, however, SLO located ƒ –‹˜ƒ–‹‘ ‘ˆ

(47) ʹ• ƒ† •—„•‡“—‡– ‹‰”ƒ–‹‘ –‘ ƒˆˆ‡ –‡† –‹••—‡• Šƒ• „‡‡ shown by other groups15,23. In sum, SLO derived signals determine migration patterns of circulating ILCs in both homeostasis and during immune activation. ILCs in shaping the adaptive immune response The most important role of SLOs in mammalian biology remains the facilitation of adaptive immune responses. In our search for the role that ILCs play in adult SLOs, we must therefore consider the adaptive immune response as an important theme. Indeed, even the localization of ILCs in the highly organized environment of the SLO has been shown to be important in that respect. ILCs mostly reside in the interfollicular regions of the SLOs1,5,6,56,57, in close contact with T cells. As such, ILCs may affect the outcome of T cell stimulation. At steady state, ILCs have been shown to suppress CD4+ T cells directed at the microbiota by presenting antigen in the absence of co174.

(48) General discussion. stimulation5,51,58,59 (chapter 5). Upon helminth infection or challenge with an allergen, ILC2s are essential for a proper Th2 response60,61, while splenic ILC3s can induce T cell responses upon immune activation62. Human SLO-derived ILC3s also express MHC-II and lack co-stimulation at steady-state, although it is not clear if this is still the case upon immune activation (chapter 5). The latter issue is of interest in case of starting immune responses, when suppression of T cells is no longer wanted. In this case, two options are conceivable. One possibility is that ILCs up-regulate co-stimulatory molecules, thereby contributing to the ongoing immune response. The other option is that ILCs dampen the response. However, ILCs are probably simply outnumbered by migratory DCs entering the T cell zone, making the chance of an encounter between a ‘relevant’ T cell and a suppressing ILC negligible. Still, the interaction between DCs, ILCs and T cells in both steady-state and upon immune activation is still of interest, as ILCs and DCs have been shown –‘ ‹ϐŽ—‡ ‡ „‡Šƒ˜‹‘” ‘ˆ ‡ƒ Š ‘–Š‡”Ǥ

(49)  ƒ†  ’‘’—Žƒ–‹‘• •—•–ƒ‹ ‡ƒ Š ‘–Š‡”‹–Š‡‹–‡•–‹‡„›•‡ ”‡–‹‘‘ˆ Ǧ ȋ

(50) •Ȍƒ†

(51) ǦͳȾȋ•Ȍ63, ILC2s ‹ϐŽ—‡ ‡ –Š‡  ’Š‡‘–›’‡ —’‘ ƒŽŽ‡”‰‡ ŠƒŽŽ‡‰‡61,64 and interactions between DCs and ILCs in SLOs have also been observed65. At mucosal •—”ˆƒ ‡•ǡ•‹ϐŽ—‡ ‡–Š‡

(52) ’Š‡‘–›’‡„›•‡ ”‡–‹‘‘ˆ‹ ‘„‹ƒ–‹‘ ™‹–Š

(53) Ǧʹ͵ƒ†

(54) ǦͳȾ14,66,67. Whether interactions between ILCs and DCs can ‹ϐŽ—‡ ‡ ‡ŽŽ’”‹‹‰„›‡‹–Š‡”•‘”

(55) •‹•‹••–‹ŽŽ–‘„‡‹˜‡•–‹‰ƒ–‡†Ǥ The residence of ILC3s in the SLOs at the border of the T cell zone with B cell follicles has implications not only for T cells, but also for B cells. Indeed, lymphotoxin (LT) production by ILCs is necessary for optimal intestinal IgA production68 and antibody production by splenic marginal zone B cells was directly and indirectly induced by ILC-derived BAFF, APRIL and GM-CSF69. In addition, IL-22 enhanced CXCL12 and CXCL13 production by follicular dendritic cells, thereby maintaining germinal centers and improving antibody production70,71. While it has not been proven that the IL-22 needed is derived from ILCs, ILC3s in SLOs are known to constitutively produce this cytokine. In combination with their location at the edge of the B cell follicles it at least implies a role for ILCs in this process. In conclusion, while ILCs represent only a minute population of CD45+ cells in SLOs, they play several roles in the shaping of the adaptive immune system.. 8. 

(56) •‹†‹•‡ƒ•‡ Defective functioning of ILCs has been implicated to play a role in the ’ƒ–Š‘‰‡‡•‹• ‘ˆ ƒ ’Ž‡–Š‘”ƒ ‘ˆ †‹•‡ƒ•‡•ǡ ”ƒ‰‹‰ ˆ”‘ ‹ϐŽƒƒ–‘”› „‘™‡Ž disease and allergies to cancer, amongst many others72. Importantly, most of the early research on ILCs in disease using mouse models was performed ‹‹—‡Ǧ†‡ϐ‹ ‹‡–‹ ‡ƒ†•Š‘—Ž†–Š‡”‡ˆ‘”‡„‡‹–‡”’”‡–‡†™‹–Š ƒ”‡Ǥ

(57)  the case of infections, their low abundance makes cytokine secretion by ILCs 175.

(58) often irrelevant in comparison with adaptive lymphocytes. Indeed, in the ’”‡•‡ ‡ ‘ˆ  ‡ŽŽ•ǡ

(59) ͵• ™‡”‡ •Š‘™ –‘ ‹ϐŽ—‡ ‡ ‘Ž› –Š‡ ”ƒ–‡ ƒ– ™Š‹ Š pathogens were cleared, if at all73-75. Researching the role of ILCs in human disease is often even more challenging as most materials obtained are either healthy or already diseased, which makes the conclusions often correlative rather than causal. Higher numbers of ILCs or enhanced cytokine production in diseased tissue may imply a causal link, but is still only circumstantial in terms of evidence. Nevertheless, ILCs have been shown to play non-redundant roles in immune activation and thus in both human and mouse pathologies. Importantly though, although some data are available on PB ILCs in humans, SLO resident ILCs have been largely disregarded in this context.

(60) —‡‡†‹ƒ–‡††‹•‡ƒ•‡ In terms of non-redundant roles for ILCs in disease, ILC2-mediated Th2 ‹†— –‹‘ ‹ ƒŽŽ‡”‰‹  ‹ϐŽƒƒ–‹‘ ‹• ’”‘„ƒ„Ž› ‘‡ ‘ˆ –Š‡ „‡•– ‡šƒ’Ž‡•Ǥ Early production of ILC2-derived IL-13 was shown to be essential for ‘†‹–‹‘‹‰ ‘ˆ • ƒ† •—„•‡“—‡– ”‡ ”—‹–‡– ‘ˆ  ‡ŽŽ• –‘ –Š‡ Ž—‰• ‘ˆ allergen-challenged mice61,64 and ILC2s directly induced Th2 skewing via antigen presentation60. In addition, ILC2s from challenged mice induced ˆ—ŽŽ„Ž‘™•‹‹ϐŽƒƒ–‹‘™Š‡–”ƒ•ˆ‡””‡†‹–‘ƒÃ˜‡‹ ‡ȋi.e., in the presence of naïve adaptive lymphocytes)76. In agreement, the presence of ILC2s is enhanced in the affected tissues of patients suffering from Th2mediated diseases such as chronic rhinosinusitis29,77 and atopic dermatitis (AD)76,78. Similar to what has been found in cohort of AD patients78, we did not observe an increase of ILC2 in PB of CHE patients, although treatment with alitretinoin did decrease PB ILC2 counts (chapter 6). Intriguingly, the population of ILC2s in PB differs in the expression of CRTH2 and CD161 as compared to the population in healthy skin76 and in skin lesions of AD patients, a population of PB-like ILC2s appeared, strengthening the ‘ ‡’––Šƒ–„Ž‘‘†Ǧ„‘” ‡ŽŽ•‹ϐ‹Ž–”ƒ–‡–‹••—‡•—’‘‹ϐŽƒƒ–‹‘ǤŠ‡–Š‡” these cells are instructed in SLOs is still to be determined, although in mice, the presence of skin draining LNs was essential for the migration of ILCs to the skin under steady-state conditions51Ǥ ‹ ‹ϐ‹Ž–”ƒ–‹‘ ‘ˆ

(61) ʹ• †—”‹‰ †‡”ƒ–‹–‹•ǦŽ‹‡ ‹ϐŽƒƒ–‹‘ ‘ —””‡† ƒŽ•‘ ‹ ‘”ɀ–-/- mice76, ƒ”‰—‹‰ ƒ‰ƒ‹•– –Š‹• ‘†‡Ž ƒŽ–Š‘—‰Š ‘”ɀ–-/- mice do not lack all SLOs79-82.

(62)  Ž‹‡ ™‹–Š †‹•–ƒ– ƒ –‹˜ƒ–‹‘ ‘ˆ

(63) • ‹ ƒ•‡ ‘ˆ ‹ϐŽƒƒ–‹‘ǡ

(64) ͵ numbers were increased in skin lesions of psoriasis patients, and activated (i.e. NKp44+) ILC3s appeared in the PB of these patients, while lacking in healthy controls53,55. This has also been observed in other cases of chronic immune activation54,83 and we have observed a reduction in expression levels of CD62L on ILCs, implying a more activated phenotype (chapter 4). An interesting observation in that respect was that ILC3s in the intestine of 176.

(65) General discussion. human Crohn’s disease patients did not express MHC-II58. In combination with the available mouse data on MHC-II-restricted antigen presentation by ILC3s being suppressive for T cells58,59, this may imply a causal role for ILC dysfunction in human IBD. These data are however still circumstantial and Žƒ ‘ˆ Ǧ

(66)

(67) ‡š’”‡••‹‘„›

(68) ͵• ƒ„‡ƒ ‘•‡“—‡ ‡‘ˆ‹ϐŽƒƒ–‹‘ rather than a cause. Our data showing that immune stimulation induces MHCII on tonsil ILC3s seems to contradict the latter statement, although in our system in some cases expression of CD80 and CD86 was induced, rendering the ILC3s in that case stimulatory rather than suppressive (chapter 5).. 8. ƒ ‡” While some roles for helper-like ILCs have been proposed, not much is known about their contribution in cancer. ILC-derived cytokines (i.e. IL-22 and IL-17) have been shown to play a role in tumorigenesis in mice, and IL-22 producing ILCs accumulate in human colorectal tumors84. On the other hand, in mouse melanoma studies, ILCs were shown to retard tumor growth85,86 although this was done in Rag-/- mice and other studies showed that the role of cytokine production by ILCs in colorectal cancer in humans ƒ†  ‡ŽŽ •—ˆϐ‹ ‹‡– ‹ ‡ ‹• ƒ”‰‹ƒŽ ƒ– „‡•–87,88. Whether the same holds true for their role in cancer immune-surveillance is an issue that should be addressed further. ‘—†Š‡ƒŽ‹‰ƒ†ȋŽ›’Š‘‹†Ȍ–‹••—‡”‡’ƒ‹” ƒ–Š‡” –Šƒ ‹ϐŽƒƒ–‹‘ ‘” –—‘”‹‰‡‡•‹•ǡ ’”‘’‡”

(69)  ˆ— –‹‘ •‡‡• –‘ be crucial for tissue repair following injury, which can also be caused by ƒ ‡šƒ‰‰‡”ƒ–‡† ‹ϐŽƒƒ–‘”› ”‡•’‘•‡Ǥ

(70) Ǧʹʹ †‡”‹˜‡† ˆ”‘

(71) ͵•ǡ „—– ‘– T cells, recruits macrophages to wound boundaries, thereby accelerating wound healing89. In much the same way, ILC3s were shown to protect the intestinal stem cell niche in grafts vs. host disease90,91 and aid in the repair ‘ˆ –Šƒ– ‹ Š‡ ƒˆ–‡” †ƒƒ‰‡ ‹ϐŽ‹ –‡† „› Š‡‘–Š‡”ƒ’›92. Likewise, in both intestines and lungs, ILC2-derived amphiregulin induces tissue repair upon ‘Ž‹–‹• ƒ† ‹ϐŽ—‡œƒ ‹ˆ‡ –‹‘ǡ ”‡•’‡ –‹˜‡Ž›93,94. Finally, focusing on SLOs, restoration of disrupted splenic microarchitecture upon infection with murine lymphocytic choriomeningitis virus was shown to be dependent on the presence of ILC3s95. In respect to the latter, an interesting observation made recently showed that NKp44+ ILC3 accumulate in human tumors. The presence of the cells correlates with density of intratumoral TLS and good prognosis96Ǥ Ž–Š‘—‰Š  ˆ‘”ƒ–‹‘ ‹ –Š‡ ‘–‡š– ‘ˆ ‹ϐŽƒƒ–‘”› diseases can occur in the absence of ILCs97-99, IL-2270 and IL-1797, as well as lymphotoxin98 have been shown to play a role in TLS formation. As all three cytokines are expressed by ILC3s, a role for these cells as initiators of TLS formation in vivo under certain circumstances cannot be excluded. 177.

(72) ĔēĈđĚĉĎēČėĊĒĆėĐĘ Although ILCs constitute only a minor population within adult SLOs, these cells play a role in shaping the adaptive immune response (chapter 5) and in maintenance, regeneration and possibly also in neogenesis of lymphoid tissue in adults. Conversely, adult SLOs provide a favorable niche for the survival of ILCs (chapter 2), and possibly play a role in the education, maturation and migration of ILCs to (epithelial) tissues (chapters 3 and 4). —‡ –‘ –Š‡‹” •ƒŽŽ —„‡”• ȋƒ† –Š—• “—‡•–‹‘ƒ„Ž‡ ”‡Ž‡˜ƒ ‡ ‹ †‹•‡ƒ•‡Ȍ ƒ† Žƒ  ‘ˆ —‹“—‡ ƒ”‡”•ǡ

(73) • ƒ”‡ –Š—• ˆƒ” ‘– •Š‘™ –‘ „‡ ƒ––”ƒ –‹˜‡ cells for therapeutic targeting. On the other hand, due to the small size of the population, changes in expression of activation or migration markers are readily detectable in PB ILCs of patients (chapter 4 and 6). This feature might be used in the future for diagnostic purposes. In conclusion, the intricate relationship between SLOs and ILCs, as supported „›–Š‡ϐ‹†‹‰•‹–Š‹•–Š‡•‹•ǡ Ž‡ƒ”Ž›”‡ƒ Š‡•ˆ—”–Š‡”–Šƒ†‡˜‡Ž‘’‡– alone and has implications for immune responses in the broadest sense. In ƒ†—Ž–•ǡ

(74) •ƒ”‡ƒ–—”‡†ǡ‹•–”— –‡†ƒ†ˆ—Žϐ‹ŽŽ–Š‡‹”‡ˆˆ‡ –‘”ˆ— –‹‘•ǡ thereby shaping adaptive immune responses. These interactions will be the •—„Œ‡ –‘ˆˆ—–—”‡‹˜‡•–‹‰ƒ–‹‘•ƒ†™‹ŽŽ•Š‡†Ž‹‰Š–‘–Š‡ϐ‹‡–—‹‰‘ˆ–Š‡ immune system in homeostasis and disease.. 178.

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(97) ϐŽƒƒ–‹‘Ǥ

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