T cells effectively respond to foreign antigens but are tolerant to self-tissues and normal enteric flora. Inappropriate activation or differentiation of T cells can lead to severe immunological disorders, including autoimmunity and inflammation. Thus, a better understanding of the molecular mechanisms regulating T-cell activation and tolerance is important for rational design of therapies for immunological diseases. The overall objective of this application is to understand the molecular and cellular mechanisms by which a newly identified deubiquitinase (DUB), CYLD, regulates T-cell function and autoimmune inflammation. During the current funding period, we have made seminal findings that establish CYLD as a pivotal regulator of T-cell activation and autoimmune inflammation. CYLD-deficient T cells are hyper-responsive to TCR stimulation, and the CYLD knockout (CYLD-/-) mice spontaneously develop intestinal inflammation with major features of human inflammatory bowel disease (IBD). The CYLD-/- mice also experience severe bone loss, which is known as a major extra-intestinal complication of IBD and animal model of colitis. Moreover, our preliminary studies reveal that loss of CYLD renders mice hypersensitive to the induction of experimental autoimmune encephalomyelitis (EAE). Thus, CYLD is a master regulator of T-cell function and autoimmune inflammatory diseases. The studies proposed in this continuation application are based on strong preliminary and published data from our laboratory. In particular, we have shown that loss of CYLD in T cells causes constitutive activation of NF-kB, a transcription factor mediating T-cell activation and survival and being involved in many inflammatory disorders. The CYLD-/- T cells also display marked attenuation of the costimulatory molecule ICOS, which is crucial for the induction of T-cell tolerance and regulation of T-cell differentiation. Consistent with these molecular studies, we have found that the CYLD-/- T cells appear to be defective in tolerance to enteric microbes, since their adoptive transfer into lymphocyte-deficient Rag1-/- mice induces severe colitis. Furthermore, the CYLD-/- mice produce aberrantly high levels of inflammatory Th17 and Th1 cells, coupled with heightened EAE response. We have obtained preliminary evidence that CYLD regulates macrophage response to TLR-stimulated expression of a specific subset of cytokines known to regulate Th1 and Th17 differentiation. Based on these findings, we hypothesize that CYLD regulates key signaling events involved in T-cell activation and differentiation as well as tolerance induction. We will perform three specific aims to accomplish our overall objective. (1) Examine the molecular mechanism and functional significance of CYLD-mediated NF-kB regulation in T cells. (2) Characterize the molecular and cellular mechanisms by which CYLD regulate T-cell tolerance and inflammatory T-cell differentiation. (3) Examine the immunological and osteoclast-intrinsic mechanisms by which CYLD regulates bone erosion.
T cells are vital for immune responses against microbial infections. However, deregulated T cell activation, due to genetic or environmental factors, can lead to severe immunological disorders, including autoimmunity and chronic inflammation. The focus of this research project is to understand how a deubiquitinase, CYLD, regulates T-cell activation and tolerance, thereby preventing the development of autoimmunity and inflammation. This knowledge is important for rational design of effective immunological therapies.
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|Jin, Jin; Xie, Xiaoping; Xiao, Yichuan et al. (2016) Epigenetic regulation of the expression of Il12 and Il23 and autoimmune inflammation by the deubiquitinase Trabid. Nat Immunol 17:259-68|
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|Zou, Qiang; Jin, Jin; Xiao, Yichuan et al. (2015) T Cell Intrinsic USP15 Deficiency Promotes Excessive IFN-Î³ Production and an Immunosuppressive Tumor Microenvironment in MCA-Induced Fibrosarcoma. Cell Rep 13:2470-9|
|Shi, Jian-hong; Sun, Shao-Cong (2015) TCR signaling to NF-ÎºB and mTORC1: Expanding roles of the CARMA1 complex. Mol Immunol 68:546-57|
|Chang, Jae-Hoon; Hu, Hongbo; Sun, Shao-Cong (2015) Survival and maintenance of regulatory T cells require the kinase TAK1. Cell Mol Immunol 12:572-9|
|Yu, Jiayi; Zhou, Xiaofei; Chang, Mikyoung et al. (2015) Regulation of T-cell activation and migration by the kinase TBK1 during neuroinflammation. Nat Commun 6:6074|
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