The Role of Notch Signaling in T Cell-mediated Immune Disorders.

[摘要] Notch is a highly conserved cell-to-cell communication pathway that plays an essential role in many biological processes. Notch exerts multiple effects in the hematopoietic system, especially during T cell development. Recent data suggest that Notch also regulates mature T cell differentiation and function. Here, we studied Notch signaling specifically in mature T cells using genetic loss-of-function approaches in two medically relevant T cell-mediated immune disorders: graft-versus-host disease (GVHD) and experimental autoimmune encephalomyelitis (EAE). We found that inhibition of Notch signaling provided long-term protection from lethal GVHD and EAE in mice.In GVHD, Notch-deprived alloreactive T cells had markedly decreased production of multiple pro-inflammatory cytokines, including IL-17A, and IFNγ, despite preserved expression of the master transcription factors T-bet and Eomesodermin. Notch-inhibited T cells acquired a hyporesponsive phenotype, but maintained in vivo expansion and cytotoxic potential. Notch1/2 and Dll1/4 mediated all the effects of Notch signaling in T cells during GVHD. Therapeutic targeting of the Notch ligands Dll1 and Dll4 prevented GVHD even with a short-course of treatment.In EAE, Notch-deprived T cells had preserved effector differentiation in secondary lymphoid organs but failed to accumulate in the central nervous system (CNS). Parking wild-type T cells with Notch-inhibited T cells allowed Notch-deprived T cells to accumulate in the CNS, although they failed to suppress disease induced by wild-type T cells. Once in the CNS, Notch-deprived T cells produced markedly decreased IL-17A and IFNγ, despite preserved T-bet expression. Collectively, these data suggest that Notch signaling augments T cell responses in a context-dependent fashion. Inhibition of cytokine production with preserved expression of master transcription factors is reminiscent of costimulation blockade in T cells in mouse models of GVHD and EAE. Notch may regulate T cell responses in a context-dependent manner by acting similarly to a costimulatory receptor. Thus, blockade of Notch signaling could be an attractive therapeutic target in T cell-mediated immune disorders.

[发布机构] University of Michigan

[效力级别] Microbiology and Immunology

[关键词] Notch in T Cell-mediated Immune Disorders;Microbiology and Immunology;Science;Immunology