Tissue-resident immune cells in homeostasis and tissue repair

Most types of immune cells are able to freely enter tissues, perform surveillance functions, and then leave them, while distinct cells are permanently located in non-lymphoid tissues. Such cells comprise tissue-resident populations (TR). Non-lymphoid tissues are home to a diverse community of innate and innate-like immune cells, such as tissue-resident macrophages (TRMφ), innate lymphocytes (ILC), γδT cells, NKT cells, MAIT cells, B1 cells, and marginal zone B cells. Previously, TR cells were thought to be derived from hematopoietic stem cells, but most TR cells are shown to be derived from erythromyeloid precursors of the yolk sac and fetal liver. TR cells have some features of “stemness”, they have the ability to self-renew, like classical hematopoietic stem cells. TR cells live in tissues due to trophic factors produced within these tissues, thus maintaining homeostasis at their microenvironment. Homeostatic factors for TRMφ are interleukin 34 (IL-34), monocyte and granulocyte-monocyte colony-stimulating factors; for ILC, γδT cells; for NKT and MAIT cells, IL-7 and IL-15; for B1 cells, IL-5. The concept of only 4 types of tissues (epithelial, connective, nervous and muscular) seems to be outdated, a more appropriate paradigm suggests existence of minimal tissue modules. In this case, each module consists of cell elements that interact with each other much more strongly than with elements outside the module. Cell associations within tissue modules provide homeostatic support to other cells that make up the module, being a niche for these cells, thus providing niche support for the former elements. Moreover, TR cells represent the first line of immune defense, since the vast majority of pathogens penetrate the body through barrier tissues. Repopulation of TR cells, that die in response to infection occurs by proliferation of the remaining TR cells, and due to migration of bone marrow-derived cells into the tissues. There are competitive relationships between these two repopulation pathways. At the same time, bone marrowderived TR cells are not capable of self-renewal and cannot fully reproduce all the functions of classical TR cells. TR cells ensure the removal of cellular debris and dead cells, regulate inflammation, remodel the extracellular matrix and produce tissue growth factors.

1. Toptygina A.P. Innate Lymphoid cells. Unknown galaxy. Rossiyskiy immunologicheskiy zhurnal = Russian Journal of Immunology, 2014, Vol. 8, no. 2, pp. 121-133. (In Russ.)

2. Toptygina A.P. Role of non-canonical T cells in homeostasis and pathology. Meditsinskaya Immunologiya = Medical Immunology (Russia), 2024, Vol. 26, no. 3, pp. 301-316. (In Russ.) doi: 10.15789/1563-0625-RON-2918.

3. Adler M., Chevan A.R., Medzhitov R. Tissue biology: in search of a new paradigm. Annu. Rev. Cell Dev. Biol., 2023, Vol. 39, pp. 67-89.

4. Ajami B., Bennett J.L., Krieger C., Tetzlaff W., Rossi F.M. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat. Neurosci., 2007, Vol. 10, pp. 1538-1543.

5. Alliot F., Godin I., Pessac B. Microglia derive from progenitors, originating from yolk sac, and which proliferate in the brain. Brain Res. Dev., 1999, Vol. 117, pp. 145-152.

6. Bain C.C., Bravo-Blass A., Scott C.L. Perdiguero E.G., Geissmann F., Henri S., Malissen B., Osborne L.C., Artis D., Mowat A.M. Constant replenishment from circulating monocytes maintains the macrophage pool in the intestine of adult mice. Nat. Immunol., 2014, Vol. 15, pp. 929-937.

7. Bank U., Deiser K., Plaza-Sirvent C., Osbelt L., Witte A., Knop L., Labrenz R., Jänsch R., Richter F., Biswas A., Zenclussen A.C., Vivier E., Romagnani C., Kühl A.A., Dunay I.R., Strowig T., Schmitz I., Schüler T. c-FLIP is crucial for IL-7/IL-15-dependent NKp46(+) ILC development and protection from intestinal inflammation in mice. Nat. Commun., 2020, Vol. 11, no. 1, 1056. doi: 10.1038/s41467-020-14782-3.

8. Benezech C., Luu N.T., Walker J.A., Kruglov A.A., Loo Y., Nakamura K., Zhang Y., Nayar S., Jones L.H., Flores-Langarica A., McIntosh A., Marshall J., Barone F., Besra G., Miles K., Allen J.E., Gray M., Kollias G., Cunningham A.F., Withers D.R., Toellner K.M., Jones N.D., Veldhoen M., Nedospasov S.A., McKenzie A.N.J., Caamaño J.H. Infammation-induced formation of fat-associated lymphoid clusters. Nat. Immunol., 2015, Vol. 16, pp. 819-828.

9. Bonnardel J., T’Jonck W., Gaublomme D., Browaeys R., Scott C.L., Martens L., Vanneste B., de Prijck S., Nedospasov S.A., Kremer A., Van Hamme E., Borghgraef P., Toussaint W., de Bleser P., Mannaerts I., Beschin A., van Grunsven L.A., Lambrecht B.N., Taghon T., Lippens S., Elewaut D., Saeys Y., Guilliams M. Stellate cells, hepatocytes, and endothelial cells imprint the kupffer cell identity on monocytes colonizing the liver macrophage niche. Immunity, 2019, Vol. 51, pp. 638-654.

10. Dutta M., Kraus Z.J., Gomez-Rodriguez J., Hwang S.H., Cannons J.L., Cheng J., Lee S.Y., Wiest D.L., Wakeland E.K., Schwartzberg P.L. A role for Ly108 in the induction of promyelocytic zinc finger transcription factor in developing thymocytes. J. Immunol., 2013, Vol. 190, pp. 2121-2128.

11. Ferrer I.R., West H.C., Henderson S., Ushakov D.S., Santos E., Sousa P., Strid J., Chakraverty R., Yates A.J., Bennett C.L. A wave of monocytes is recruited to replenish the long-term Langerhans cell network after immune injury. Sci. Immunol., 2019, Vol. 4, eaax8704. doi: 10.1126/sciimmunol.aax8704.

12. Garner L. C., Klenerman P., Provine N.M. Insights into mucosal-associated invariant t cell biology from studies of invariant natural killer T cells. Front. Immunol., 2018, Vol. 9, 1478. doi: 10.3389/fimmu.2018.01478.

13. Ghaedi M., Shen Z.Y., Orangi M., Martinez-Gonzalez I., Wei L., Lu X., Das A., Heravi-Moussavi A., Marra M.A., Bhandoola A., Takei F. Single-cell analysis of RORa tracer mouse lung reveals ILC progenitors and effector ILC2 subsets. J. Exp. Med., 2020, Vol. 217, no. 3, jem.20182293. doi: 10.1084/jem.20182293.

14. Ghosn E.E., Yamamoto R., Hamanaka S., Yang Y., Herzenberg L.A., Nakauchi H., Herzenberg LA. Distinct B-cell lineage commitment distinguishes adult bone marrow hematopoietic stem cells. Proc. Natl. Acad. Sci. USA, 2012, Vol. 109, pp. 5394-5398.

15. Ginhoux F., Greter M., Leboeuf M., Nandi S., See P., Gokhan S., Mehler M.F., Conway S.J., Ng L.G., Stanley E.R., Samokhvalov I.M., Merad M. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science, 2010, Vol. 330, pp. 841-845.

16. Ginhoux F., Guilliams M. Tissue-resident macrophage ontogeny and homeostasis. Immunity, 2016, Vol. 44, pp. 439-449.

17. Ginhoux F., Schultze J.L., Murray P.J., Ochando J., Biswas S.K. New insights into the multidimensional concept of macrophage ontogeny, activation and function. Nat. Immunol., 2015, Vol. 17, pp. 34-40.

18. Gordy L.E., Bezbradica J.S., Flyak A.I., Spencer C.T., Dunkle A., Sun J., Stanic l.K., Boothby M.R., He Y.-W., Zhao Z., van Kaer L., Joyce S. IL-15 regulates homeostasis and terminal maturation of NKT cells. J Immunol., 2011, Vol. 187, no. 12, pp. 6335-6345.

19. Guilliams M., De Kleer I., Henri S., Post S., Vanhoutte L., De Prijck S., Deswarte K., Malissen B., Hammad H., Lambrecht B.N. Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the week of life via GM-CSF. J. Exp. Med. 2013, Vol. 210, pp. 1977-1992.

20. Guilliams M., Thierry G.R., Bonnardel J., Bajenoff M. Establishment and maintenance of the macrophage niche. Immunity, 2020, Vol. 52, pp. 434-451.

21. Haas J.D., Ravens S., Duber S., Sandrock I., Oberdorfer L., Kashani E., Chennupati V., Fohse L., Naumann R., Weiss S., Krueger A, Förster R, Prinz I. Development of interleukin-17-producing γδ T cells is restricted to a functional embryonic wave. Immunity, 2012, Vol. 37, pp. 48-59.

22. Hardy R.R., Hayakawa K. A developmental switch in B lymphopoiesis. Proc. Natl. Acad. Sci. USA, 1991, Vol. 88, pp. 11550-11554.

23. Hoeffel G., Ginhoux F. Ontogeny of tissue-resident macrophages. Front. Immunol., 2015, Vol. 6, 486. doi: 10.3389/fimmu.2015.00486.

24. Hoeffel G., Wang Y., Greter M., See P., Teo P., Malleret B., Leboeuf M., Low D., Oller G., Almeida F., Choy S.H., Grisotto M., Renia L., Conway S.J., Stanley E.R., Chan J.K., Ng L.G., Samokhvalov I.M., Merad M., Ginhoux F. Adult Langerhans cells derive predominantly from embryonic fetal liver monocytes with a minor contribution of yolk sak-derived macrophages. J. Exp. Med., 2012, Vol. 209, pp 1167-1181.

25. Jagannathan-Bogdan M., Zon L.I. Hematopoiesis. Development, 2013, Vol. 140, pp. 2463-2467. 26. Koay H.-F., Godfrey D.I., Pellicci D.G. Development of mucosal-associated invariant T cells. Immunol. Cell Biol., 2018, Vol. 96, no. 6, pp. 598-606.

26. Kristiansen T.A., Jaensson Gyllenback E., Zriwil A., Bjorklund T., Daniel J.A., Sitnicka E., Soneji S., Bryder D., Yuan J. Cellular barcoding links B-1a B cell potential to a fetal hematopoietic stem cell state at the single-cell level. Immunity., 2016, Vol. 45, pp. 346-357.

27. Krovi S.H., Gapin L. Invariant natural killer t cell subsets – more than just developmental intermediates. Front. Immunol., 2018, Vol. 9, 1393. doi: 10.3389/fimmu.2018.01393.

28. Lazarov T., Juarez-Carreño S., Cox N., Geissmann F. Physiology and diseases of tissue-resident macrophages. Nature, 2023, Vol. 618, no. 7966, pp. 698-707.

29. Liu C., Gong Y., Zhang H., Yang H., Zeng Y., Bian Z., Xin Q., Bai Z., Zhang M., He J., Yan J., Zhou J., Li Z., Ni Y., Wen A., Lan Y., Hu H., Liu B. Delineating spatiotemporal and hierarchical development of human fetal innate lymphoid cells. Cell Res., 2021, Vol. 31, pp. 1106-1122.

30. Liu H., Leo C., Chen X., Wong B.R., Williams L.T., Lin H., He X. The mechanism of shared but distinct CSF-1R signaling by the non-homologous cytokines IL-34 and CSF-1. Biochim. Biophys. Acta, 2012, Vol. 1824, pp. 938-945.

31. Machiels B., Dourcy M., Xiao X., Javaux J., Mesnil C., Sabatel C., Des mecht D., Lallemand F., Martinive P., Hammad H., Guilliams M., Dewals B., Vanderplasschen A., Lambrecht B.N., Bureau F., Gillet L. A gamma herpesvirus provides protection against allergic asthma by inducing the replacement of resident alveolar macrophages with regulatory monocytes. Nat. Immunol., 2017, Vol. 18, pp. 1310-1320.

32. Mattos M.S., Vandendriessche S., Waisman A., Marques P.E. The immunology of B-1 cells: from development to aging. Immun Ageing, 2024, Vol. 21, 54. doi: 10.1186/s12979-024-00455-y.

33. Meher A.K., McNamara C.A. B-1 lymphocytes in adipose tissue as innate modulators of inflammation linked to cardiometabolic disease. Immunol. Rev., 2024, Vol. 324, no. 1, pp. 95-103.

34. Moro K., Yamada T., Tanabe M., Takeuchi T., Ikawa T., Kawamoto H., Furusawa J., Ohtani M., Fujii H., Koyasu S. Innate production of T(H)2 cytokines by adipose tissue-associated c-kit(+)Sca-1(+) lymphoid cells. Nature, 2010, Vol. 463, no. 7280, pp. 540-544.

35. Muñoz-Garcia J., Cochonneau D., Télétchéa S., Moranton E., Lanoe D., Brion R., Lézot F., Heymann M.F., Heymann D. The twin cytokines interleukin-34 and CSF-1: masterful conductors of macrophage homeostasis. Theranostics, 2021, Vol. 11, no. 4, pp. 1568-1593.

36. Nandi M., Moyo M.M., Orkhis S., Mobulakani J.M.F., Limoges M.A., Rexhepi F., Mayhue M., Cayarga A.A., Marrero G.C., Ilangumaran S., Menendez A., Ramanathan S. IL-15Ralpha-Independent IL-15 Signaling in NonNK Cell-Derived IFNgamma driven control of listeria monocytogenes Front. Immunol., 2021, Vol. 12, 793918. doi: 10.3389/fimmu.2021.793918.

37. Pridans C., Raper A., Davis G.M., Alves J., Sauter K.A., Lefevre L., Regan T., Meek S., Sutherland L., Thomson A.J., Clohisey S., Bush S.J., Rojo R., Lisowski Z.M., Wallace R., Grabert K., Upton K.R., Tsai Y.T., Brown D., Smith L.B., Summers K.M., Mabbott N.A., Piccardo P., Cheeseman M.T., Burdon T., Hume D.A. Pleiotropic impacts of macrophage and microglial deficiency on development in rats with targeted mutation og the Csf1r locus. J. Immunol., 2018, Vol. 201, pp. 2683-2699.

38. Ramond C., Berthault C., Burlen-Defranoux O., de Sousa A.P., Guy-Grand D., Vieira P., Pereira P., Cumano A. Two waves of distinct hematopoietic progenitor cells colonize the fetal thymus. Nat. Immunol., 2014, Vol. 15, pp. 27-35.

39. Sawai C.M., Babovic S., Upadhaya S., Knapp D.J., Lavin Y., Lau C.M., Goloborodko A., Feng J., Fujisaki J., Ding L., Mirny L.A., Merad M., Eaves C.J., Reizis B. Hematopoietic stem cells are the major source of multilineage hematopoiesis in adult animals. Immunity, 2016, Vol. 45, pp. 597-609.

40. Scott C.L., Zheng F., de Baetselier P., Martens L., Saeys Y., de Prijck S., Lippens S., Abels C., Schoonooghe S., Raes G., Devoogdt N., Lambrecht B.N., Beschin A., Guilliams M. Bone marrow derived monocytes give rise to self-renewing and fully differentiated Kupffer cells. Nat. Commun., 2016, Vol. 7, 10321. doi: 10.1038/ncomms10321.

41. Simic M., Manosalva I., Spinelli L., Gentek R., Shayan R.R., Siret C., Girard-Madoux M., Wang S., de Fabritus L., Verschoor J., Kerdiles Y.M., Bajenoff M., Stumm R., Golub R., van de Pavert S.A. Distinct waves from the hemogenic endothelium give rise to layered lymphoid tissue inducer cell ontogeny. Cell Rep., 2020, Vol. 32, 108004. doi: 10.1016/j.celrep.2020.108004.

42. Stehle C., Rückert T., Fiancette R., Gajdasik D.W., Willis C., Ulbricht C., Durek P., Mashreghi M.F., Finke D., Hauser A.E., Withers D.R., Chang H.D., Zimmermann J., Romagnani C. T-bet and RORa control lymph node formation by regulating embryonic innate lymphoid cell differentiation. Nat. Immunol, 2021, Vol. 22, pp. 1231-1244.

43. Webster K.E., Kim H.O., Kyparissoudis K., Corpuz T.M., Pinget G.V., Uldrich A.P., Brink R., Belz G.T., Cho J.H., Godfrey D.I., Sprent J. IL-17-producing NKT cells depend exclusively on IL-7 for homeostasis and survival. Mucosal Immunol., 2014, Vol. 7, no. 5, pp. 1058-1067.

44. Winer H., Rodrigues G.O.L., Hixon J.A., Aiello F.B., Hsu T.C., Wachter B.T., Li W., Durum S.K. IL-7. Comprehensive review. Cytokine, 2022, Vol. 160, 156049. doi: 10.1016/j.cyto.2022.156049.

45. Xian L., Wu X., Pang L., Lou M., Rosen C.J., Qiu T., Crane J., Frassica F., Zhang L., Rodriguez J.P., Jia X., Yakar S., Xuan S., Efstratiadis A., Wan M., Cao X. Matrix IGF-1 maintains bone mass by activation of mTOR in mesenchymal stem cells. Nat. Med., 2012, Vol. 18, pp. 1095-1101.

46. Xu W., Cherrier D.E., Chea S., Vosshenrich C., Serafini N., Petit M., Liu P., Golub R., di Santo J.P. An Id2RFPreporter mouse redefines innate lymphoid cell precursor potentials. Immunity, 2019, Vol. 50, pp. 1054-1068.e3.

47. Yao G.Q., Troiano N., Simpson C.A., Insogna K.L. Selective deletion of the soluble Colony-Stimulating Factor 1 isoform in vivo prevents estrogen-deficiency bone loss in mice. Bone Res., 2017, Vol. 5, 170. doi: 10.1038/boneres.2017.22.

48. Yoshimoto M. The ontogent of murine B-1a cells. Int. J. Hematol., 2020, Vol. 11, no. 5, pp. 622-627.

49. Zeis P., Lian M., Fan X., Herman J.S., Hernandez D.C., Gentek R., Elias S., Symowski C., Knöpper K., Peltokangas N., Friedrich C., Doucet-Ladeveze R., Kabat A.M., Locksley R.M., Voehringer D., Bajenoff M., Rudensky A.Y., Romagnani C., Grün D., Gasteiger G. In situ maturation and tissue adaptation of type 2 innate lymphoid cell progenitors. Immunity, 2020, Vol. 53, pp. 775-792.e9.

50. Zhu Q., Gao P., Tober J., Bennett L., Chen C., Uzun Y., Li Y., Howell E.D., Mumau M., Yu W., He B., Speck N.A., Tan K. Developmental trajectory of prehematopoietic stem cell formation from endothelium. Blood, 2020, Vol. 136, pp. 845-856.