Regulation Of Immune Cell Survival And Differentiation By β-catenin And The Underlying Mechanisms

Partâ… Fibronectin promotes NK cell survival viaβ-catenin pathwayTissue microenvironment and stroma-derived extracellular matrix(ECM)molecules play important roles in the survival and differentiation of cells.Mouse naturalkiller(NK)cells usually die within 24 hours once isolated ex vivo.Exogenouscytokines such as interleukin(IL)-12 and IL-15 are required to maintain the survivaland activity of mouse NK cells cultured in vitro.However,whether and how ECMmolecules such as fibronectin can support the survival of NK cells remain unknown.Here we demonstrate that fibronectin,just like IL-15,can maintain survival of mouseNK cells in vitro.Furthermore,we show that fibronectin binds to the CDllb on NKcells,and then CD11b recruits and activates Src.Src can directly interact withβ-cateninand trigger nuclear translocation ofβ-catenin.The activation ofβ-catenin promotesERK phosphorylation,resulting in the increased expression of anti-apoptotic proteinBcl-2 which may contribute to the maintenance of NK cell survival.Consistently,fibronectin can not maintain the survival of CDllb negative NK cells andβ-catenin-deficient NK cells sorted from in vivo,and the number of NK cell isdramatically decreased in theβ-catenin-deficient mice.Therefore,fibronectin canmaintain survival of mouse NK cells by activating ERK and upregulating Bcl-2expression via CD11b/Src/β-catenin pathway. Partâ…¡TLR 4,9 signals-recruited regulatory monocytes maintainhomeostasis of regulatory T cells through membrane bound TGF-βandβ-catenin pathwaySeveral Toll-like receptor(TLR)agonists play protective roles in the pathogenesisof autoimmune diseases and asthma.It has been found that constant exposure to lowconcentration of some TLR agonists contributes to the maintenance of an essentialnumber of CD4+Foxp3+regulatory T cell(Treg)in vivo,giving a reasonableexplanation for the protective role of TLR signals.However,the cellular and molecularmechanisms of TLR signals involved in regulating the expression of Foxp3 in CD4⁺Tcells remain unclear up to now.Here,we demonstrate that a new population ofGr-1^highLy-6C^intmonocytes with regulatory function,triggered by TLR4,9 ligands,canpromot generation of CD4⁺Foxp3⁺Treg.TLR4,9 ligands could recruite Gr-1^highLy-6C^intmonocytes from bonce marrow via stimulating the release of NO and upregulatedexpression of membrane-bound TGF-βon Gr-1^highLy-6C^intmonocytes.Membrane-bound TGF-βon Gr-1^highLy-6C^intmonocytes induces Foxp3 expression in CD4⁺CD25^-Tcells by activatingβ-catenin-dependent STAT3 pathway.Compared to wild-typeCD4⁺CD25^-T cells,β-catenin^-/-CD4⁺CD25^-T cells could not be induced to differentiateinto CD4⁺Foxp3⁺Treg by Gr-1^highLy-6C^intmonocytes.Furthermore,in clean condition,TLR4^-/-and TLR9^-/-mice acquire severer inflammatory bowel disease(IBD)after DSStreatment,while in SPF condition,TLR signals play a protective role in DSS-induceddevelopment of IBD.Thus,we conclude that TLR signals are required for controllingautoimmune responses viaβ-catenin/STAT3-dependent induction of Treg by inducinggeneration of a new subset of Gr-1^highLy-6C^intregulatory monocytes.