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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
3R01AI064639-08S1
Application #
8715065
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Lapham, Cheryl K
Project Start
2005-04-01
Project End
2015-06-30
Budget Start
2013-08-01
Budget End
2014-06-30
Support Year
8
Fiscal Year
2013
Total Cost
$109,171
Indirect Cost
$40,939
Name
University of Texas MD Anderson Cancer Center
Department
Microbiology/Immun/Virology
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Chang, Jae-Hoon; Hu, Hongbo; Jin, Jin et al. (2014) TRAF3 regulates the effector function of regulatory T cells and humoral immune responses. J Exp Med 211:137-51
Nakaya, Mako; Xiao, Yichuan; Zhou, Xiaofei et al. (2014) Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation. Immunity 40:692-705
Yu, Jiayi; Zhou, Xiaofei; Nakaya, Mako et al. (2014) T cell-intrinsic function of the noncanonical NF-?B pathway in the regulation of GM-CSF expression and experimental autoimmune encephalomyelitis pathogenesis. J Immunol 193:422-30
Xiao, Yichuan; Jin, Jin; Chang, Mikyoung et al. (2014) TPL2 mediates autoimmune inflammation through activation of the TAK1 axis of IL-17 signaling. J Exp Med 211:1689-702
Zou, Qiang; Jin, Jin; Hu, Hongbo et al. (2014) USP15 stabilizes MDM2 to mediate cancer-cell survival and inhibit antitumor T cell responses. Nat Immunol 15:562-70
Jin, Jin; Hu, Hongbo; Li, Haiyan S et al. (2014) Noncanonical NF-?B pathway controls the production of type I interferons in antiviral innate immunity. Immunity 40:342-54
Xiao, Yichuan; Jin, Jin; Chang, Mikyoung et al. (2013) Peli1 promotes microglia-mediated CNS inflammation by regulating Traf3 degradation. Nat Med 19:595-602
Hu, Hongbo; Brittain, George C; Chang, Jae-Hoon et al. (2013) OTUD7B controls non-canonical NF-*B activation through deubiquitination of TRAF3. Nature 494:371-4
Sun, Shao-Cong; Chang, Jae-Hoon; Jin, Jin (2013) Regulation of nuclear factor-*B in autoimmunity. Trends Immunol 34:282-9
Sun, Shao-Cong (2012) Immune receptor signaling: from ubiquitination to NF-*B activation. Cell Mol Immunol 9:97-8

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