T cell homeostasis and tolerance are governed by proper orchestration of multiple factors expressed on T cells, including antigen receptors, costimulatory molecules and inhibitory molecules. In addition, T cell tolerance is controlled via cell-cell interactions with antigen presenting cells of a certain status (e.g., immature or mature dendritic cells) or by regulatory T cells. The major goal of this proposal is to understand how T cell tolerance or fate is controlled, in particular, via cell-intrinsic means. This application stems from our preliminary data on the role of the signaling adapter TRAF6 in T cells. Our preliminary data, generated from TRAF6 conditional knockout mice crossed to CD4-cre transgenic mice (TRAF6-deltaT), show that when TRAF6 is deleted in T cells mice develop splenomegaly and lymphadenopathy associated with T cell hyperproliferation. These results imply that (i) TRAF6 has a previously unrecognized, cell-intrinsic role in T lymphocytes, and (ii) TRAF6 may act as a """"""""negative"""""""" regulator of T cell homeostasis. These results are quite unexpected since immunoreceptors utilizing TRAF6, such as CD40 or IL-1/Toll-like receptors (TLRs), are mostly implicated in the regulation of ARC function. Hence, we propose to extend the study of T cell biology, as regulated by TRAF6, by pursuing the following aims: (i) to determine cellular defects leading to the lymphoproliferative disease observed in TRAF6-deltaT mice, (ii) to determine molecular defects of T cells lacking TRAF6, and (iii) to utilize TRAF6-deltaT mice possessing defined antigen specificity to determine how TRAF6 regulates T cells during maturation and activation, and how this relates to the defect in immune homeostasis. The proposed studies should define a previously unrecognized mechanism(s) for how T cell tolerance and fate are controlled at the molecular and cellular level. Such studies will provide the basis for novel intervention strategies against various autoimmune diseases and for new methods to enhance T cell immune responses against cancer.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Cellular and Molecular Immunology - A Study Section (CMIA)
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Lapham, Cheryl K
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University of Pennsylvania
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Walsh, Matthew C; Takegahara, Noriko; Kim, Hyunsoo et al. (2018) Updating osteoimmunology: regulation of bone cells by innate and adaptive immunity. Nat Rev Rheumatol 14:146-156
Han, Daehee; Walsh, Matthew C; Kim, Kwang Soon et al. (2017) Dendritic cell expression of the signaling molecule TRAF6 is required for immune tolerance in the lung. Int Immunol 29:71-78
Lin, Jiqiang; Yang, Lu; Silva, Hernandez Moura et al. (2016) Increased generation of Foxp3(+) regulatory T cells by manipulating antigen presentation in the thymus. Nat Commun 7:10562
Walsh, Matthew C; Lee, JangEun; Choi, Yongwon (2015) Tumor necrosis factor receptor- associated factor 6 (TRAF6) regulation of development, function, and homeostasis of the immune system. Immunol Rev 266:72-92
Park, Eui-Soon; Choi, Seunga; Shin, Bongjin et al. (2015) Tumor necrosis factor (TNF) receptor-associated factor (TRAF)-interacting protein (TRIP) negatively regulates the TRAF2 ubiquitin-dependent pathway by suppressing the TRAF2-sphingosine 1-phosphate (S1P) interaction. J Biol Chem 290:9660-73
Han, Daehee; Walsh, Matthew C; Kim, Kwang Soon et al. (2015) Microbiota-independent ameliorative effects of antibiotics on spontaneous th2-associated pathology of the small intestine. PLoS One 10:e0118795
Lin, Jingjing; Lee, Daekee; Choi, Yongwon et al. (2015) The scaffold protein RACK1 mediates the RANKL-dependent activation of p38 MAPK in osteoclast precursors. Sci Signal 8:ra54
Ko, Ryeojin; Park, Jin Hee; Ha, Hyunil et al. (2015) Glycogen synthase kinase 3? ubiquitination by TRAF6 regulates TLR3-mediated pro-inflammatory cytokine production. Nat Commun 6:6765
Lee, Jang Eun; Walsh, Matthew C; Hoehn, Kyle L et al. (2015) Acetyl CoA Carboxylase 2 Is Dispensable for CD8+ T Cell Responses. PLoS One 10:e0137776
Lee, JangEun; Walsh, Matthew C; Hoehn, Kyle L et al. (2014) Regulator of fatty acid metabolism, acetyl coenzyme a carboxylase 1, controls T cell immunity. J Immunol 192:3190-9

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