You can follow Dr. Watts on Twitter: @Tania_WattsUofT
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 TNFR family members on T cells binding to TNF superfamily ligands on inflammatory antigen presenting cells, provide a critical post-priming checkpoint (signal 4), to allow T cell accumulation during viral infection.4 A current focus is to understand how type I interferons induce distinct patterns of costimulatory molecule expression in different types of antigen presenting cell in mice and humans 4,5. We are currently working 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.6-8
My laboratory has a strong interest in T cell immunity in humans, with an emphasis on influenza and, more recently, SARS CoV-2. 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.9 We also examined the state of immunity to A/2009 pandemic influenza in the Toronto population at 1 year post-pandemic.10 We recently compared recall responses to SARS-CoV-2 antigens as compared to memory responses to influenza in patients that had recovered from COVID1911 and have shown that these responses persist at least 9 months. 12 We are now studying how drugs that modulate autoimmune and inflammatory diseases affect vaccination to COVID19.
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,13 however, it can negatively regulate TLR signaling to limit inflammation.14 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. 15
Our research is funded by the Canadian Institutes of Health Research, the COVID-19 immunity task force, the Canadian Cancer Society, and by a donation from the Speck family.
2. Snell, L.M., Lin, G.H., McPherson, A.J., Moraes, T.J. & Watts, T.H. T-cell intrinsic effects of GITR and 4-1BB during viral infection and cancer immunotherapy. Immunological reviews 244, 197-217 (2011).
5. Girard, M., Law, J.C., Edilova, M.I. & Watts, T.H. Type I interferons drive the maturation of human DC3s with a distinct costimulatory profile characterized by high GITRL. Sci Immunol 5, eabe0347 (2020)
6. Zhou, A.C., Wagar, L.E., Wortzman, M.E. & Watts, T.H. 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 10, 1294-1309 (2017).
7. Chu, K.L., Batista, N.V., Wang, K.C., Zhou, A.C. & Watts, T.H. GITRL on inflammatory antigen presenting cells in the lung parenchyma provides signal 4 for T-cell accumulation and tissue-resident memory T-cell formation. Mucosal Immunol 12, 363-377 (2019).
8. Zhou, A.C., Batista, N.V. & Watts, T.H. 4-1BB Regulates Effector CD8 T Cell Accumulation in the Lung Tissue through a TRAF1-, mTOR-, and Antigen-Dependent Mechanism to Enhance Tissue-Resident Memory T Cell Formation during Respiratory Influenza Infection. J. Immunol. 202, 2482-2492 (2019).
9. Wagar, L.E., Gentleman, B., Pircher, H., McElhaney, J.E. & Watts, T.H. 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 (2011).
13. McPherson, A.J., Snell, L.M., Mak, T.W. & Watts, T.H. Opposing roles for TRAF1 in the alternative versus classical NF-kappaB pathway in T cells. The Journal of biological chemistry 287, 23010-23019 (2012).
- Canada Research Chair (Tier 1) in anti-viral immunity 2021-2028
- Director, Faculty of Medicine flow cytometry facility
- Associate Chair, Post-Doctoral Program
Honours and Awards
- Distinguished fellow of the American Association of Immunologists, class of 2022
- 2009-2019 Sanofi Pasteur Chair in Human Immunology (endowed chair)
- 2019 JJ Berry-Smith Doctoral Supervision Award (University of Toronto)
- 2018 Canadian Society for Immunology John D. Reynolds Award
- 2016 Canadian Society for Immunology Bernhard Cinader Award
- 2014 GSK Fast Track Challenge Winner
- 2006 Canadian Society for Immunology Investigator Award
- 1998-2003 Senior Scientist of the National Cancer Institute of Canada
- 1986-1991 Medical Research Council of Canada Scholar