Function And Regulation Of The Sin1-mTORC2 Signals In Intestinal Group 2 Innate Lymphoid Cells

Innate lymphoid cells(ILCs)were recently identified innate immune cells that widely reside at mucosal surfaces of the body.ILCs could quickly respond to pathogens or allergens,involved in immune response,inflammation,metabolism and tissue repair.ILCs resemble the CD4+T helper(Th)cells in transcriptional factor expression and cytokine production but lack the specific antigen receptor.Group 2 innate lymphoid cells(ILC2s)are a subset of innate lymphoid cells(ILCs)and share properties with T helper type 2(Th2)cells,they both express the GAT A3 and secret type Ⅱ cytokine such as IL5,IL-13.ILC2s are key participants in type 2 immune responses in the context of worm infection,allergic inflammation,tissue repair and metabolic homeostasis regulation.The serine/threonine kinase mammalian target of rapamycin(mTOR)is a central integrator of multiple intracellular and extracellular signals including growth factors,cytokines,nutrients and plays important roles in cell growth,proliferation and metabolism.mTOR performs different cellular functions by forming two distinct multi-protein mTOR complexes(mTORC),mTORCl and mTORC2.mTORCl promote protein synthesis and ribosome biogenesis,while mTORC2 regulate cell growth,survival,metabolism and cytoskeletal rearrangement.mTORCs have been widely studied as a crucial regulator in the immuce cell development,differentiation and cellular function.However,little is known of mTORCs,especially the mTORC2 in modulation of ILC development,cell growth,maintenance and function.In our study,we found that Sin1,an essential component of mTORC2,plays a critical role in maintaining the numbers of ILC2s in intestinal lamina propria.Deletion of Sin]resulted in a dramatic reduction of ILC2 number and ratio but not ILC3 or T cells.Using mixed BM transfer strategy,mature ILC2 transfer experiments and parabiosis model,we demonstrated that Sin]regulates ILC2 local proliferation in a cell-intrinsic manner.Mechanismly,we found that via regulating pRB-E2F1 axis activation,Sin1 contributes to ILC2 cell cycle related gene expression to promote proliferation then maintain the normal ILC2 number and proportion;Meanwhile,Sin1 could modulate ILC2 lipid storage and mitochondria oxidative phosphorylation.Furthermore,we found the intestinal Neuromedin U(NMU)could induce pAKT473 phosphorylation,Sin1 could mediate Nmu23 induced ILC2 growth in vitro.Functionally,with the Nippostrongylus brasiliensis infection mouse model,we revealed that the absence of Sin1 leads to delayed worm expulsion and impaired type Ⅱ immune response,caused by a decrease of ILC2s.Our study identified Sin1-mTORC2 as a key regulator of ILC2 proliferation and metabolism that control ILC2 maintenance and anti-worm function.