Research InterestsAdaptive Immunity, Infectious Diseases, T-cells
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TNFR family members and TRAF proteins in viral infection, inflammation and cancer
Upon an infection, the innate and then the adaptive immune system are rapidly ramped up to control and then clear the infection. T cell activation requires the recognition of an antigen-MHC complex by the T cell receptor (signal 1) along with a costimulatory signal from CD28 (signal 2) and additional signals from cytokines (signal 3). When T cells are activated, they upregulate members of the tumor necrosis factor receptor (TNFR) superfamily. Our laboratory has had a long-standing interest in this family of receptors, which play important roles in controlling life and death in the immune system (1-3). An overriding question in our laboratory is why we need TNFR family members in addition to CD28 family molecules during viral infection. Our recent data, show that TNFR family members on T cells binding to TNF superfamily ligands on inflammatory monocyte-derived antigen presenting cells, provide a critical post-priming checkpoint (signal 4), to allow T cell accumulation during viral infection (4).
The persistent induction of stimulatory TNFR superfamily members on T cells during chronic infection raised the question of how the immune system avoids excessive TNFR family stimulation. Our laboratory has shown that TNFR family signaling is tightly controlled during chronic infection. In the case of the costimulatory TNFR family member 4-1BB, the pathway becomes desensitized during chronic viral infection, through loss of a key signaling adaptor TRAF1 (5). In contrast, within a few days of a chronic viral infection, the TNF family ligand GITRL is downregulated below baseline (4, 6) An ongoing focus in the lab is to identify the signals induced by GITR and 4-1BB to sustain T cell activation, so that we can understand the unique and overlapping features of these costimulatory pathways.
Another area of interest is the role of TNFR family members in tissue resident memory T cells (Trm). Trm persist in the tissues after clearance of infection to provide a first line of defense upon re-infection. Our recent results show that 4-1BB is critical for the formation lung resident memory CD8 T cells (Trm) and that inclusion of 4-1BBL into a vaccine vector delivered intranasally greatly enhances the establishment of the Trm population and its persistence (7). We are currently investigating the mechanisms by which 4-1BB contributes to Trm formation.
My laboratory has a strong interest in T cell immunity in humans, with an emphasis on influenza and HIV. For example, we explored the state of T cell memory to influenza virus in older people and found that the memory CD8 T cells expressed markers of terminal differentiation and senescence commonly found in T cells specific for persisting pathogens such as CMV (8). We also examined the state of immunity to A/2009 pandemic influenza in the Toronto population at 1 year post-pandemic (9).
Another aspect of our work has been to investigate the role of TNFR associated factors (TRAFs) in TNFR signaling and human disease. TRAF1 has diverse roles in biology; it is a critical positive regulator of 4-1BB signaling, (10) however, it can negatively regulate TLR signaling to limit inflammation (11) TRAF1 is also expressed in human lymphoma and chronic lymphocytic leukemia and an ongoing project in the lab involves a therapeutic approach to lower TRAF1 levels in cancer cells.
Our research is funded by a Canadian Institutes for Health Foundation Grant.
Tania Watts holds the Sanofi Pasteur chair in Human Immunology at the University of Toronto
Publications and Awards
- Watts TH. TNF/TNFR family members in costimulation of T cell responses. Ann Rev Immunol 2005, 23: 23-68.
- Snell LM, Lin GH, McPherson AJ, Moraes TJ, Watts TH. T-cell intrinsic effects of GITR and 4-1BB during viral infection and cancer immunotherapy. Immunological reviews 2011, 244(1): 197-217.
- Clouthier DL, Watts TH. TNFRs and Control of Chronic LCMV Infection: Implications for Therapy. Trends Immunol 2015, 36(11): 697-708.
- Chang Y-H, Wang K, K-L C, Clouthier DL, Tran AT, Torres Perez MS, . . . Watts TH. Dichotomous expression of TNF Superfamily Ligands on Antigen-Presenting Cells Controls Post-priming Anti-viral CD4+ T cell Immunity. Immunity 2017, 47: 943-958.
- Wang C, McPherson AJ, Jones RB, Kawamura KS, Lin GH, Lang PA, . . . Watts TH. Loss of the signaling adaptor TRAF1 causes CD8+ T cell dysregulation during human and murine chronic infection. The Journal of experimental medicine 2012, 209(1): 77-91.
- Clouthier DL, Zhou AC, Watts TH. Anti-GITR Agonist Therapy Intrinsically Enhances CD8 T Cell Responses to Chronic Lymphocytic Choriomeningitis Virus (LCMV), Thereby Circumventing LCMV-Induced Downregulation of Costimulatory GITR Ligand on APC. J Immunol 2014, 193(10): 5033-5043.
- Zhou AC, Wagar LE, Wortzman ME, Watts TH. Intrinsic 4-1BB signals are indispensable for the establishment of an influenza-specific tissue-resident memory CD8 T-cell population in the lung. Mucosal Immunol 2017, 10(5): 1294-1309.
- Wagar LE, Gentleman B, Pircher H, McElhaney JE, Watts TH. Influenza-specific T cells from older people are enriched in the late effector subset and their presence inversely correlates with vaccine response. PloS one 2011, 6(8): e23698.
- Wagar LE, Rosella L, Crowcroft N, Lowcock B, Drohomyrecky PC, Foisy J, . . . Watts TH. Humoral and cell-mediated immunity to pandemic H1N1 influenza in a Canadian cohort one year post-pandemic: implications for vaccination. PloS one 2011, 6(11): e28063.
- McPherson AJ, Snell LM, Mak TW, Watts TH. Opposing roles for TRAF1 in the alternative versus classical NF-kappaB pathway in T cells. The Journal of biological chemistry 2012, 287(27): 23010-23019.
- Abdul-Sater AA, Edilova MI, Clouthier DL, Mbanwi A, Kremmer E, Watts TH. The signaling adaptor TRAF1 negatively regulates Toll-like receptor signaling and this underlies its role in rheumatic disease. Nat Immunol 2017, 18(1): 26-35.