Research InterestsAdaptive Immunity, Infectious Diseases, T-cells
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TNFR family members and TRAF proteins in viral infection and cancer
Upon an infection, the innate and then the adaptive immune system are rapidly ramped up to control and then clear the infection. When T cells are activated, in addition to developing effector functions that aid in clearing of the infection, they also upregulate members of the tumor necrosis factor receptor (TNFR) family. This family of receptors plays an important role in controlling life and death in the immune system. An overriding question in our laboratory is why we need TNFR family members in addition to CD28 family molecules during viral infection. Evidence to date suggests that TNFR family members provide a post-priming checkpoint to sustain T cell responses while antigens persist (1-3). However, this raised the question of how the immune systems avoids excessive costimulation. 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 (4). In contrast, the TNF family ligand GITRL, becomes downregulated below baseline, a few days into chronic viral infection (5). A current focus in the lab is to identify key signals induced by GITR versus 4-1BB to sustain T cell activation and to understand the unique features of each of these costimulatory pathways. We are also interested in delineating where and when the TNF family ligands engage the T cells. Another area of interest is the role of TNFR family members in T cell memory. Our recent results show that 4-1BB is critical for the formation lung resident memory CD8 T cells (Trm) (6) and we are currently investigating the mechanism by which 4-1BB contributes to Trm formation.
My laboratory also has a strong interest in T cell immunity in humans, with an emphasis on influenza and HIV. In recent studies, we have 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 (7). We also examined the state of immunity to A/2009 pandemic influenza in the Toronto population at 1 year post-pandemic (8).
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 (9), however, it can negatively regulate TLR signaling to limit inflammation (10). TRAF1 is also expressed in human lymphoma and CLL and another project in the lab involves studying the role of TRAF1 in cancer. Further work is aimed at understanding the mechanisms of TRAF1 function in cancer and autoimmunity.
Our research is funded by the Canadian Institutes for Health . Tania Watts holds the Sanofi Pasteur chair in Human Immunology at the University of Toronto
Publications and Awards
- Snell, L. M., G. H. Lin, A. J. McPherson, T. J. Moraes, and T. H. Watts. 2011. T-cell intrinsic effects of GITR and 4-1BB during viral infection and cancer immunotherapy. Immunological reviews 244: 197-217.
- Lin, G. H., B. J. Sedgmen, T. J. Moraes, L. M. Snell, D. J. Topham, and T. H. Watts. 2009. Endogenous 4-1BB ligand plays a critical role in protection from influenza-induced disease. J. Immunol. 182: 934-947.
- Clouthier, D. L., A. C. Zhou, M. E. Wortzman, O. Luft, G. A. Levy, and T. H. Watts. 2015. GITR Intrinsically Sustains Early Type 1 and Late Follicular Helper CD4 T Cell Accumulation to Control a Chronic Viral Infection. PLoS Pathog 11: e1004517.
- Wang, C., A. J. McPherson, R. B. Jones, K. S. Kawamura, G. H. Lin, P. A. Lang, T. Ambagala, M. Pellegrini, T. Calzascia, N. Aidarus, A. R. Elford, F. Y. Yue, E. Kremmer, C. M. Kovacs, E. Benko, C. Tremblay, J. P. Routy, N. F. Bernard, M. A. Ostrowski, P. S. Ohashi, and T. H. Watts. 2012. Loss of the signaling adaptor TRAF1 causes CD8+ T cell dysregulation during human and murine chronic infection. The Journal of experimental medicine 209: 77-91.
- Clouthier, D. L., A. C. Zhou, and T. H. Watts. 2014. 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. 193: 5033-5043.
- Zhou, A. C., L. E. Wagar, M. E. Wortzman, and T. H. Watts. 2016. 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 in press.
- Wagar, L. E., B. Gentleman, H. Pircher, J. E. McElhaney, and T. H. Watts. 2011. Influenza-specific T cells from older people are enriched in the late effector subset and their presence inversely correlates with vaccine response. PloS one 6: e23698.
- Wagar, L. E., L. Rosella, N. Crowcroft, B. Lowcock, P. C. Drohomyrecky, J. Foisy, J. Gubbay, A. Rebbapragada, A. L. Winter, C. Achonu, B. J. Ward, and T. H. Watts. 2011. Humoral and cell-mediated immunity to pandemic H1N1 influenza in a Canadian cohort one year post-pandemic: implications for vaccination. PloS one 6: e28063.
- McPherson, A. J., L. M. Snell, T. W. Mak, and T. H. Watts. 2012. Opposing roles for TRAF1 in the alternative versus classical NF-kappaB pathway in T cells. The Journal of biological chemistry 287: 23010-23019.
- Abdul-Sater, A. A., M. I. Edilova, D. L. Clouthier, A. Mbanwi, E. Kremmer, and T. H. Watts. 2016. The signaling adaptor TRAF1 negatively regulates Toll-like receptor signaling and this underlies its role in rheumatic disease. Nat. Immunol. in press. 10.1038/ni.3618