Research InterestsAdaptive Immunity, Infectious Diseases, T-cells
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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 (1). This family of receptors plays an important role in controlling life and death in the immune system. Our lab has shown that the TNFR family members 4-1BB and GITR are critical for sustaining CD8 T cell survival in the lung during acute severe respiratory influenza infection (2, 3). We provided evidence that the immune system uses antigen–inducible TNFRs such as 4-1BB to control the duration of T cell response according to the persistence of the virus, thereby allowing a response that is sufficient to clear the virus, but is down regulated once the virus is cleared to protect the host from pathology (2, 4, 5). This led us to ask what happens when the virus cannot be cleared, such as occurs with HIV infection of humans or lymphocytic choriomeningitis virus clone 13 infection of mice.
In the event that a virus cannot be eliminated from the host, immune regulatory mechanisms come into play that allow a détente to be reached between the host and pathogen, thereby balancing immune control of the pathogen against collateral damage. We showed that although 4-1BB expression persists on the LCMV specific CD8 T cells at the chronic phase of infection with the clone 13 variant of LCMV, the 4-1BB signaling pathway becomes desensitized due to loss of one of its key signaling adaptors, TRAF1 (6). TRAF1 is also lost from HIV specific T cells with progression of HIV, but maintained at higher levels in those individuals that can control their HIV infection(6). Moreover, the TRAF1 levels inversely correlate with viral load. In contrast, we showed that the TNFR family member GITR is differentially regulated during viral infection (3, 7, 8). GITR is turned off during chronic viral infection through persistent downregulation of its ligand, GITRL. Future work in our laboratory will investigate the underlying mechanisms behind the differential role of TNFRs in different infections.
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. We found that the presence of this influenza specific KLRG1hiCD57hi T cell population was a predictor of a poor antibody response to vaccination to seasonal H1N1 influenza (9). We also examined the state of immunity to A/2009 pandemic influenza in the Toronto population at 1 year post-pandemic(10).
Another aspect of our work has been to investigate the role of TNFR signaling in lymphocyte survival. We showed that the signaling adaptor TRAF1 was critical for the survival of activated T cells (11, 12). However, others had shown TRAF1 is a negative regulator of immunity. Recently we resolved this paradox by showing that TRAF1 is a positive regulator of classical NF-κB signaling downstream of 4-1BB In T cells, but negatively regulates the alternative NF-κB and cytokine productions in anti-CD3 activated T cells (13). Current projects in our lab are investigating the role of TRAF1 in several human diseases, including cancer, autoimmunity and HIV.
Our research is funded by the Canadian Institutes for Health Research and the Canadian Cancer Society.
Publications and Awards
- Watts, T. H. 2005. TNF/TNFR family members in costimulation of T cell responses. Ann. Rev. Immunol. 23: 23-68.
- 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.
- Snell, L. M., A. J. McPherson, G. H. Lin, S. Sakaguchi, P. P. Pandolfi, C. Riccardi, and T. H. Watts. 2010. CD8 T Cell-Intrinsic GITR Is Required for T Cell Clonal Expansion and Mouse Survival following Severe Influenza Infection. J. Immunol. 185: 7223-7234.
- 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.
- Wang, C., G. H. Lin, A. J. McPherson, and T. H. Watts. 2009. Immune regulation by 4-1BB and 4-1BBL: complexities and challenges. Immunol Rev 229: 192-215.
- 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., 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.
- 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.
- 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.
- Sabbagh, L., C. C. Srokowski, G. Pulle, L. M. Snell, B. J. Sedgmen, Y. Liu, E. N. Tsitsikov, and T. H. Watts. 2006. A critical role for TNF receptor-associated factor 1 and Bim down-regulation in CD8 memory T cell survival. Proc Natl Acad Sci U S A 103: 18703-18708.
- Wang, C., T. Wen, J. P. Routy, N. F. Bernard, R. P. Sekaly, and T. H. Watts. 2007. 4-1BBL induces TNF receptor-associated factor 1-dependent Bim modulation in human T cells and is a critical component in the costimulation-dependent rescue of functionally impaired HIV-specific CD8 T cells. J. Immunol. 179: 8252-8263.
- 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.