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Innate production of TH2 cytokines by adipose tissue-associated c-Kit+Sca-1+ lymphoid cells

Abstract

Innate immune responses are important in combating various microbes during the early phases of infection. Natural killer (NK) cells are innate lymphocytes that, unlike T and B lymphocytes, do not express antigen receptors but rapidly exhibit cytotoxic activities against virus-infected cells and produce various cytokines1,2. Here we report a new type of innate lymphocyte present in a novel lymphoid structure associated with adipose tissues in the peritoneal cavity. These cells do not express lineage (Lin) markers but do express c-Kit, Sca-1 (also known as Ly6a), IL7R and IL33R. Similar lymphoid clusters were found in both human and mouse mesentery and we term this tissue ‘FALC’ (fat-associated lymphoid cluster). FALC Lin-c-Kit+Sca-1+ cells are distinct from lymphoid progenitors3 and lymphoid tissue inducer cells4. These cells proliferate in response to IL2 and produce large amounts of TH2 cytokines such as IL5, IL6 and IL13. IL5 and IL6 regulate B-cell antibody production and self-renewal of B1 cells5,6,7. Indeed, FALC Lin-c-Kit+Sca-1+ cells support the self-renewal of B1 cells and enhance IgA production. IL5 and IL13 mediate allergic inflammation and protection against helminth infection8,9. After helminth infection and in response to IL33, FALC Lin-c-Kit+Sca-1+ cells produce large amounts of IL13, which leads to goblet cell hyperplasia—a critical step for helminth expulsion. In mice devoid of FALC Lin-c-Kit+Sca-1+ cells, such goblet cell hyperplasia was not induced. Thus, FALC Lin-c-Kit+Sca-1+ cells are TH2-type innate lymphocytes, and we propose that these cells be called ‘natural helper cells’.

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Figure 1: Lin -c-Kit +Sca-1 + cells exist in FALCs.
Figure 2: c-Kit +Sca-1 + cells of FALCs are a new lymphocyte population.
Figure 3: FALC c-Kit +Sca-1 + cells produce T H2 cytokines and support B1 cell proliferation.
Figure 4: FALC c-Kit +Sca-1 + cells produce IL5 and IL13 in response to IL33 and induce goblet cell hyperplasia after helminth infection.

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References

  1. Lodoen, M. B. & Lanier, L. L. Natural killer cells as an initial defence against pathogens. Curr. Opin. Immunol. 18, 391–398 (2006)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Andoniou, C. E., Andrews, D. M. & Degli-Esposti, M. A. Natural killer cells in viral infection: more than just killers. Immunol. Rev. 214, 239–250 (2006)

    Article  CAS  PubMed  Google Scholar 

  3. Kawamoto, H. & Katsura, Y. A new paradigm for hematopoietic cell lineages: revision of the classical concept of the myeloid-lymphoid dichotomy. Trends Immunol. 30, 193–200 (2009)

    Article  CAS  PubMed  Google Scholar 

  4. Nishikawa, S., Honda, K., Vieira, P. & Yoshida, H. Organogenesis of peripheral lymphoid organs. Immunol. Rev. 195, 72–80 (2003)

    Article  CAS  PubMed  Google Scholar 

  5. Sonoda, E. et al. Transforming growth factor β induces IgA production and acts additively with interleukin 5 for IgA production. J. Exp. Med. 170, 1415–1420 (1989)

    Article  CAS  PubMed  Google Scholar 

  6. Beagley, K. W. et al. Interleukins and IgA synthesis. Human and murine interleukin 6 induce high rate IgA secretion in IgA-committed B cells. J. Exp. Med. 169, 2133–2148 (1989)

    Article  CAS  PubMed  Google Scholar 

  7. Erickson, L. D., Foy, T. M. & Waldschmidt, T. J. Murine B1 B cells require IL-5 for optimal T cell-dependent activation. J. Immunol. 166, 1531–1539 (2001)

    Article  CAS  PubMed  Google Scholar 

  8. Knight, P. A., Brown, J. K. & Pemberton, A. D. Innate immune response mechanisms in the intestinal epithelium: potential roles for mast cells and goblet cells in the expulsion of adult Trichinella spiralis . Parasitology 135, 655–670 (2008)

    Article  CAS  PubMed  Google Scholar 

  9. Fallon, P. G. et al. Identification of an interleukin (IL)-25-dependent cell population that provides IL-4, IL-5, and IL-13 at the onset of helminth expulsion. J. Exp. Med. 203, 1105–1116 (2006)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Cao, X. et al. Defective lymphoid development in mice lacking expression of the common cytokine receptor γ chain. Immunity 2, 223–238 (1995)

    Article  CAS  PubMed  Google Scholar 

  11. Tsuji, M. et al. Requirement for lymphoid tissue-inducer cells in isolated follicle formation and T cell-independent immunoglobulin A generation in the gut. Immunity 29, 261–271 (2008)

    Article  CAS  PubMed  Google Scholar 

  12. Rangel-Moreno, J. et al. Omental milky spots develop in the absence of lymphoid tissue-inducer cells and support B and T cell responses to peritoneal antigens. Immunity 30, 731–7343 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Schmitz, J. et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 23, 479–490 (2005)

    Article  CAS  PubMed  Google Scholar 

  14. Watanabe, Y. et al. A murine thymic stromal cell line which may support the differentiation of CD4-8- thymocytes into CD4+8- αβ T cell receptor positive T cells. Cell. Immunol. 142, 385–397 (1992)

    Article  CAS  PubMed  Google Scholar 

  15. Sanos, S. L. et al. RORγt and commensal microflora are required for the differentiation of mucosal interleukin 22-producing NKp46+ cells. Nature Immunol. 10, 83–91 (2009)

    Article  CAS  ADS  Google Scholar 

  16. Yokota, Y. et al. Development of peripheral lymphoid organs and natural killer cells depends on the helix–loop–helix inhibitor Id2. Nature 397, 702–706 (1999)

    Article  CAS  ADS  PubMed  Google Scholar 

  17. Eberl, G. et al. An essential function for the nuclear receptor RORγt in the generation of fetal lymphoid tissue inducer cells. Nature Immunol. 5, 64–73 (2004)

    Article  CAS  Google Scholar 

  18. Arend, W. P., Palmer, G. & Gabay, C. IL-1, IL-18, and IL-33 families of cytokines. Immunol. Rev. 223, 20–38 (2008)

    Article  CAS  PubMed  Google Scholar 

  19. Kroeger, K. M., Sullivan, B. M. & Locksley, R. M. IL-18 and IL-33 elicit Th2 cytokines from basophils via a MyD88- and p38α-dependent pathway. J. Leukoc. Biol. 86, 769–778 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Humphreys, N. E., Xu, D., Hepworth, M. R., Liew, F. Y. & Grencis, R. K. IL-33, a potent inducer of adaptive immunity to intestinal nematodes. J. Immunol. 180, 2443–2449 (2008)

    Article  CAS  PubMed  Google Scholar 

  21. Wang, Y. H. et al. IL-25 augments type 2 immune responses by enhancing the expansion and functions of TSLP-DC-activated Th2 memory cells. J. Exp. Med. 204, 1837–1847 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Haraldsen, G., Balogh, J., Pollheimer, J., Sponheim, J. & Küchler, A. M. Interleukin-33—cytokine of dual function or novel alarmin? Trends Immunol. 30, 227–233 (2009)

    Article  CAS  PubMed  Google Scholar 

  23. Wood, I. S., Wang, B. & Trayhurn, P. IL-33, a recently identified interleukin-1 gene family member, is expressed in human adipocytes. Biochem. Biophys. Res. Commun. 384, 105–109b (2009)

    Article  CAS  PubMed  Google Scholar 

  24. Voehringer, D., Reese, T. A., Huang, X., Shinkai, K. & Locksley, R. M. Type 2 immunity is controlled by IL-4/IL-13 expression in hematopoietic non-eosinophil cells of the innate immune system. J. Exp. Med. 203, 1435–1446 (2006)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Nocka, K. et al. Molecular bases of dominant negative and loss of function mutations at the murine c-kit/white spotting locus: W37, Wv, W41 and W . EMBO J. 9, 1805–1813 (1990)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hayashi, C., Sonoda, T., Nakano, T., Nakayama, H. & Kitamura, Y. Mast-cell precursors in the skin of mouse embryos and their deficiency in embryos of Sl/Sld genotype. Dev. Biol. 109, 234–241 (1985)

    Article  CAS  PubMed  Google Scholar 

  27. Miyawaki, S. et al. A new mutation, aly, that induces a generalized lack of lymph nodes accompanied by immunodeficiency in mice. Eur. J. Immunol. 24, 429–434 (1994)

    Article  CAS  PubMed  Google Scholar 

  28. Shinkai, Y. et al. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell 68, 855–867 (1992)

    Article  CAS  PubMed  Google Scholar 

  29. Kennedy, M. K. et al. Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice. J. Exp. Med. 191, 771–780 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Suzuki, H., Duncan, G. S., Takimoto, H. & Mak, T. W. Abnormal development of intestinal intraepithelial lymphocytes and peripheral natural killer cells in mice lacking the IL-2 receptor β chain. J. Exp. Med. 185, 499–505 506 (1997)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Maki, K. et al. Interleukin 7 receptor-deficient mice lack T cells. Proc. Natl Acad. Sci. USA 93, 7172–7177 (1996)

    Article  CAS  ADS  PubMed  PubMed Central  Google Scholar 

  32. Yoshida, H. et al. Expression of α4β7 integrin defines a distinct pathway of lymphoid progenitors committed to T cells, fetal intestinal lymphotoxin producer, NK, and dendritic cells. J. Immunol. 167, 2511–2521 (2001)

    Article  CAS  PubMed  Google Scholar 

  33. Ishiwata, K. & Watanabe, N. Nippostrongylus brasiliensis: reversibility of reduced-energy status associated with the course of expulsion from the small intestine in rats. Exp. Parasitol. 117, 80–86 (2007)

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Y. Yokota and H. Kiyono for Id2-/- mice, D. Littman and S. Fagarasan for RorcGFP/GFP mice, T. W. Mak for Il2/15rb-/- mice, K. Ikuta for Il7-/- mice, and K. Ishiwata for N. brasiliensis. Thanks are also owed to L. K. Clayton for critical reading of the manuscript and valuable suggestions, M. Fujiwara for help with microarray analysis, Y. Baba and A. Minowa for help with some experiments, and K. Takei and K. Hidaka for animal care. This work was supported by a Keio University Grant-in-Aid for Encouragement of Young Medical Scientists (to K.M.), a Grant-in Aid for Young Scientist (B) (20790378 to K.M.), Grants-in-Aid for Scientific Research (B) (14370116, 16390146, 18390155 to S.K.) from the Japan Society for the Promotion of Science, and a Scientific Frontier Research Grant from the Ministry of Education, Culture, Sports, Science and Technology, Japan. K.M. is a postdoctoral fellow of the Global COE program supported by the Ministry of Education, Culture, Sports, Science and Technology, Japan.

Author Contributions K.M. conceived the study, performed experimental work, and wrote the paper; T.Y. performed the pathological work; M.T. and T.T. performed the helminth infection experiments; T.I. and H.K. performed the lymphoid progenitor assay; J.-i.F., M.O. and H.F. performed experiments, interpreted data and provided intellectual input; and S.K. conceived the study and wrote the paper.

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Correspondence to Shigeo Koyasu.

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S.K. is a consultant for Medical and Biological Laboratories, Co. Ltd.

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Moro, K., Yamada, T., Tanabe, M. et al. Innate production of TH2 cytokines by adipose tissue-associated c-Kit+Sca-1+ lymphoid cells. Nature 463, 540–544 (2010). https://doi.org/10.1038/nature08636

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