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

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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 H 2 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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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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