Duerr, Claudia U

Hamann, Antonia A

Helfrich, Sofia

Less, Christiane

English

Institutional Repository of the Freie Universität Berlin

NEWS AND COMMENTARY OPENTo the lymph node and beyond: migratory ILC3s regulateinnate and adaptive immune responsesSofia Helfrich , Antonia A Hamann , Christiane Less & Claudia U Duerr*Department of Microbiology, Infectious Diseases and Immunology, Freie Universit€at Berlin and Humboldt-Universit€at zu Berlin, Charite –Universit€atsmedizin Berlin, Berlin, GermanyImmunology & Cell Biology 2021; 99: 442–445; doi: 10.1111/imcb.12457An important characteristic ofimmune cells is their ability tocirculate through the body scoutingfor pathogens, transformed cells orother potential insults. However,helper-like innate lymphoid cells(ILCs) have been identified asprimarily tissue resident. Helper-likeILCs are a recently described set ofcell populations composed of threefunctionally diverse subgroups:ILC1s, ILC2s and ILC3s.1 ILCsexhibit striking functional similaritiesto adaptive T cells includingexpression of subgroup-specificsignature cytokines and transcriptionfactors. However, ILCs do not expressrearranged antigen receptors and areactivated in an antigen-independentmanner by cytokines, neuropeptides,leukotrienes and otherimmunomodulators. With theirstrategic positioning at barriersurfaces and their immediate way ofinitiating effector mechanisms, ILCsare able to rapidly shape their tissuemicroenvironment and orchestrateinnate as well as adaptive immuneresponses. Importantly, ILCsthemselves are imprinted by localenvironmental cues and adopt tissue-specific phenotypes that allow themto tailor their functional capacities tothe anatomical niche they reside in.While considered mainly tissueresident, ILC progenitors as well asmature ILCs exhibit limitedmigratory potential to home to theirrespective organ during development,to strategically position themselveswithin an organ or to replenish theexhausted ILC tissue pool. Inaddition, interorgan trafficking ofILCs has been described.2 Moreover,identification of human circulatingILC progenitors has led to furtherdiscussion about ILC motility.3Increasing evidence is also emergingthat ILCs are able to directly orindirectly trigger adaptive immuneresponses, which could be promotedby an ILC migration potential.Whereas T-cell trafficking is welldocumented, the understanding ofILC motility remains incompletelyunderstood.ILCs represent a rare cellpopulation and thus addressing theirmigration is experimentally extremelychallenging. In a recent issue ofMucosal Immunology, K€astele et al.4studied ILC migration by usingKaede photoconvertible mice. Kaedemice are genetically manipulatedtransgenic mice, which express Kaedeprotein. In Kaede micephotoconversion takes place uponexposure to low-intensity violet lightand red labelled cells can be identifiedas resident cells by the Kaede redprotein, whereas migrating and thusnot photoconverted cells areidentified by the Kaede green protein.Kaede mice are therefore importantin vivo imaging models to monitorcellular motility within an organ orbetween different organs. Strikingly,all ILCs within Kaede mice canactively migrate to lymph nodes, afundamental cellular processpreviously unknown.However, the extent of motility bythe ILC groups is different dependingon the health status. It has beenpreviously shown that ILCs can befound in the lymph. The lymph andthe lymphatics build an importantnetwork and connect differentorgans, yet determining the origin ofcells in the lymph remains highlyelusive. K€astele et al. applied anadvanced technique by cannulatingthe thoracic duct and harvestingmigrating cells, enabling lymph to becollected from the efferentlymphatics. Lymph was also collectedafter removal of the mesentericlymph node, mimicking pseudo-afferent lymphatics. This elegantmethod enabled cells entering thelymphatics from the tissue or thelymph node to be distinguished,which has never been investigatedbefore. Applying these novel models,a significant population of migratoryILCs could be identified in the lymphnode, even if at a lower frequencycompared with T cells, their adaptivecounterpart. With these elegant andnovel techniques, the researcherscould not only investigate the*CorrespondenceClaudia U Duerr, Department ofMicrobiology, Infectious Diseases andImmunology, Freie Universit€at Berlin andHumboldt-Universit€at zu Berlin, Charite –Universit€atsmedizin Berlin,Hindenburgdamm 30, 12003 Berlin,Germany.E-mail: claudia.duerr@charite.de442Immunology & Cell Biology 2021; 99: 442–445www.wileyonlinelibrary.com/journal/icb 14401711, 2021, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/imcb.12457 by Charité - Universitaetsmedizin, Wiley Online Library on [25/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons Licensemotility of ILCs but also encouragefurther research into cell migratorypatterns between as well as withinorgans.The number of migrating ILCsduring infection or conditions ofinflammation remains poorlyunderstood, as does a completeunderstanding of migration potentialof all ILC populations. K€astele et al.quantitatively addressed whichintestinal ILC populations aremigrating at steady state as well asunder acute inflammatoryconditions, demonstrating for thefirst time that all ILC subsets couldmigrate under homeostasis. ILC1srepresented the main ILCpopulation trafficking at steady state,confirming previous data, with mostmigrating from the mesentericlymph nodes.5 Interestingly, ILC2s,ILC3s and T-bet+ ILC3s were alsotrafficking to a similar extent fromthe mesenteric lymph nodes. Duringinfection, interferon-c (IFN-c)responses are crucial in the defenseagainst Salmonella.6 Indeed, K€asteleet al. identified that migratory ILCsincreased expression of several IFNregulatory factors, indicating ILCsmay contribute to the resolution ofan intestinal bacterial infectionthrough their IFN signature.Whereas the immune activationphenotype of migrating ILCs atsteady state and upon infectionremained similar, IFN-c andgranulocyte–macrophage colony-stimulating factor (GM-CSF)coexpression were more pronouncedupon infection in the draininglymph node, suggesting that ILCsare actively participating in creatinga microenvironment in the lymphnode to trigger immune responsesand resolution of an intestinalbacterial infection. Altogether, theresearch team has provided adynamic overview and thus keyinsights into spatial–temporalpatterns of trafficking of ILCs as rarecell populations, which weretypically considered tissue residentonly (Figure 1).The work by K€astele et al.revealed for the first time that ILCs,albeit at small numbers, are enteringthe lymph and can migrate to thedraining lymph node of the intestineunder homeostatic conditions.Importantly, the ability of ILCs totraffic to the mesenteric lymph nodewas observed to be independent ofthe state of health, although uponinflammation the composition ofmigrating ILC subgroups as well astheir activation profile subsequentlychanged. This indicates that themigration and activation profile isindeed influenced by infection;however, the number may be limitedby intercellular dynamics. The abilityof migratory ILC3s to express IFN-calone as well as in combination withGM-CSF suggests that they maydirectly contribute to the defenseagainst Salmonella Typhimurium.Indeed, IFN-c production is key inS. Typhimurium infection.6 Here,ILC3-derived IFN-c has been shownto regulate goblet cell formation andinflammatory response uponSalmonella infection.7 In addition,ILC3-derived granulocyte–macrophage colony-stimulatingfactor GM-CSF is important torecruit inflammatory monocytes,trigger dendritic cells and promoteacute intestinal inflammation.8K€astele et al. now in detailinvestigated the activation andcytokine profile of migratory ILC3s,linking their capacity to dislocate tothe LN as well as their characteristiccytokine profile to fight off intestinalpathogens. Importantly, previouswork9,10 has shown that ILCs,including ILC2s and ILC3s, arelocated in the interfollicular regionsof lymph nodes. K€astele et al.confirmed this observation andadditionally demonstrated that ILCsmigrate via the lymph to reach thisarea. CCR7 and CD62L have beenpreviously implicated in themigration of ILC progenitors as wellas trafficking of ILC1s to the lymphnode.5,11 Importantly, migration ofLymphoid Tissue inducer (LTI)-likeILC3s, a distinct subpopulation ofILC3s, was shown to be CCR7dependent upon infection with theparasite Heligmosomoides polygyrus.9Upregulation of CCR7 transcriptexpression was also observed byunbiased RNA-Seq analysiscomparing tissue-resident ILCs inthe lamina propria with migratorylymph ILCs, further highlighting thepotential role of this chemokinereceptor in ILC migration via thelymph. It is evident now that ILCsutilize the lymphatic system totraffic to other organs. However, theprecise functional role of ILCs in thelymph node remains elusive. DuringCitrobacter rodentium infection,ILC3s have been shown to play akey role by triggering T-follicularhelper responses andimmunoglobulin A production.10Based on their specific location, ILCscould influence T-cell responses aswell as the development andrecruitment of myeloid cells inSalmonella infection by productionof IFN-c or GM-CSF, respectively.Moreover, splenic IFN-c has beenrecently reported to trigger MHC-IIexpression by LTi-like ILC3s andthereby T-cell activation.12 T-bet+ILC3-released IFN-c may therebyimpact LTi-like ILC3 responses inthe intestinal lymph node uponSalmonella infection. Interestingly,ILC3s are also present in otherlymph nodes including the lung-draining mediastinal lymph nodes,9although ILC2s represent thedominant helper ILC population atthis site, highlighting their potentialto direct adaptive immuneresponses.In this study, K€astele et al. clearlydemonstrate that all investigated ILCpopulations are able to migrate fromthe intestinal tissue to the lymphnode at steady state as well as under443S Helfrich et al. Migratory ILC3s regulate innate and adaptive immune responses 14401711, 2021, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/imcb.12457 by Charité - Universitaetsmedizin, Wiley Online Library on [25/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons Licenseinflammatory conditions. However,not all ILC subgroups traffic to thesame extent and the exactunderlying mechanisms that triggermigration of ILC3s specifically uponSalmonella infection and retentionin, but also egress of ILCs from thelymph node remain unclear.Interestingly, K€astele et al. identifiedan IFN signature on migrating ILC3supon infection. IFN may be animportant candidate, which couldinfluence restraining of ILC2s andaffect the migration of ILC3s in adirect or indirect manner. However,to what extent IFN affects themigration of ILCs still needs to beelucidated. The acquisition ofantigen by ILC3s together withadditional (maturation) signals maybe important in Salmonellainfection. Interestingly, ILCmigration and positioning in thelymph node has been shown to beregulated by the receptor GPR183sensing cholesterol metabolites suchas oxysterol.10 Whether this is alsothe case for ILC3s upon Salmonellainfection is not known.Furthermore, whether changes innutrient or microbiota compositionaffect ILC3 migration andpositioning in the lymph node uponSalmonella infection, and how theirretention in the lymph node mayregulate adaptive immune responsesrequire further investigation. Overall,the ability of ILCs to migrate to theLN, their expression of cytokinesand their positioning are of greatinterest. Active regulation of theseprocesses may be a target ofFigure 1. Migratory ILC3s travel in the lymph and trigger immune responses upon infection. The scheme depicts the findings by K€astele et al. AllILC groups are able to migrate via the lymph under homeostasis. Upon acute Salmonella infection, increased numbers of T-bet+ ILC3s traffic inthe lymph and are present in the mesenteric lymph node expressing IFNc alone or in combination with GM-CSF. The work raises several keyquestions for future studies, which are highlighted in the figure by question marks: Which mechanisms trigger ILC3 migration? Do ILC3scollaborate with each other upon infection? How is ILC egress regulated? T-bet+ ILC3s are depicted in dark green and LTi-like ILC3s in lightgreen, ILC1s in red and ILC2s in blue. LTi, Lymphoid Tissue inducer; GM-CSF, granulocyte–macrophage colony-stimulating factor; IFN, interferon;ILC, innate lymphoid cell.444Migratory ILC3s regulate innate and adaptive immune responses S Helfrich et al. 14401711, 2021, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/imcb.12457 by Charité - Universitaetsmedizin, Wiley Online Library on [25/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons Licensescientific and clinical interest tocounteract adverse immunopathologiesof the intestine.ACKNOWLEDGMENTSThe work was supported by the GermanResearch Foundation (DFG; SPP1937-DU 1295/4-1) and WOA Institution:Charite Universitatsmedizin Berlin.Open access funding was enabled andorganized by Projekt DEAL.REFERENCES1. Vivier E, Artis D, Colonna M, et al.Innate Lymphoid Cells: 10 YearsOn. Cell 2018; 174: 1054–1066.2. Willinger T. Metabolic Control ofInnate Lymphoid Cell Migration.Front Immunol 2019; 10: 2010.3. Lim AI, Li Y, Lopez-Lastra S, et al.Systemic Human ILC PrecursorsProvide a Substrate for Tissue ILCDifferentiation. Cell 2017; 168(1086–1100): e1010.4. K€astele V, Johannes Mayer J, LeeES, et al. Intestinal-derived ILCsmigrating in lymph increase IFN-cproduction in response toSalmonella Typhimurium. MucosalImmunol 2021. https://doi.org/10.1038/s41385-020-00366-3. Onlineahead of print5. Dutton EE, Gajdasik DW, Willis C,et al. Peripheral lymph nodescontain migratory and residentinnate lymphoid cell populations.Sci Immunol 2019; 4: eaau8082.6. Bao S, Beagley KW, France MP,Shen J, Husband AJ. Interferon-cplays a critical role in intestinalimmunity against Salmonellatyphimurium infection. Immunology2000; 99: 464–472.7. Klose CS, Kiss EA, Schwierzeck V,et al. A T-bet gradient controls thefate and function of CCR6–RORc+innate lymphoid cells. Nature 2013;494: 261–265.8. Pearson C, Thornton EE, McKenzieB, et al. ILC3 GM-CSF productionand mobilisation orchestrate acuteintestinal inflammation. Elife 2016;5: e10066.9. Mackley EC, Houston S, MarriottCL, et al. CCR7-dependenttrafficking of RORc+ ILCs creates aunique microenvironment withinmucosal draining lymph nodes. NatCommun 2015; 6: 5862.10. Melo-Gonzalez F, Kammoun H,Evren E, et al. Antigen-presentingILC3 regulate T cell-dependent IgAresponses to colonic mucosal bacteria.J Exp Med 2019; 216: 728–742.11. Bar-Ephraim YE, Koning JJ,Burniol Ruiz E, et al. CD62L Is aFunctional and Phenotypic Markerfor Circulating Innate LymphoidCell Precursors. J Immunol 2019;202: 171–182.12. Lehmann FM, von Burg N, IvanekR, et al. Microbiota-induced tissuesignals regulate ILC3-mediatedantigen presentation. Nat Commun2020; 11: 1794.ª 2021 The Authors. Immunology & Cell Biologypublished by John Wiley & Sons Australia, Ltd onbehalf of Australian and New Zealand Society forImmunology, Inc.This is an open access article under the terms ofthe Creative Commons Attribution License, whichpermits use, distribution and reproduction in anymedium, provided the original work is properlycited.445S Helfrich et al. Migratory ILC3s regulate innate and adaptive immune responses 14401711, 2021, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/imcb.12457 by Charité - Universitaetsmedizin, Wiley Online Library on [25/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

To the lymph node and beyond: migratory ILC3s regulate innate and adaptive immune responses

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To the lymph node and beyond: migratory ILC3s regulate innate and adaptive immune responses

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