Tania Watts

Please note: Dr. Watts is not currently accepting new students in her lab, at this time.

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  TNF family ligands are regulated by type I interferons.^4,5 A current area of interest is to ask how we can manipulate these signals to induce  long lived T cell memory in the respiratory tract to protect against influenza.  Our recent results show that 4-1BB is critical for the formation lung resident memory CD8 T cells and that inclusion of 4-1BBL in 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 compared recall responses to SARS-CoV-2 antigens as compared to memory responses to influenza in patients that had recovered from COVID19⁹ and have shown that these responses persist at least 9 months with an altered phenotype in the SARS-CoV-2-specific compared to influenza A specific T cell responses. ¹⁰  We are also investigating the impact of treatment with immune modulators for autoimmune diseases on the immunogenicity of SARS-CoV-2 vaccines. ¹¹

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,¹² however, it can negatively regulate TLR signaling to limit inflammation.¹³  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. ¹⁴

Our research is funded by the Canadian Institutes of Health Research, the COVID-19 immunity task force,  and by a donation from the Speck family.

PUB MED search:

https://www.ncbi.nlm.nih.gov/pubmed?cmd=search&term=Watts+TH

Selected references

1.         Watts, T.H. TNF/TNFR family members in costimulation of T cell responses. Ann. Rev. Immunol. 23, 23-68. (2005).

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).

3.         Clouthier, D.L. & Watts, T.H. TNFRs and Control of Chronic LCMV Infection: Implications for Therapy. Trends Immunol 36, 697-708 (2015).

4.         Chang, Y.H., et al. Dichotomous Expression of TNF Superfamily Ligands on Antigen-Presenting Cells Controls Post-priming Anti-viral CD4(+) T Cell Immunity. Immunity 47, 943-958 e949 (2017).

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.         Law, J.C., et al. Systematic Examination of Antigen-Specific Recall T Cell Responses to SARS-CoV-2 versus Influenza Virus Reveals a Distinct Inflammatory Profile. J. Immunol. 206, 37-50 (2021).

10.       Law, J.C., et al. Persistence of T Cell and Antibody Responses to SARS-CoV-2 Up to 9 Months after Symptom Onset. J. Immunol. 208, 429-443 (2022).

11.       Dayam, R.M., et al. Accelerated waning of immunity to SARS-CoV-2 mRNA vaccines in patients with immune-mediated inflammatory diseases. JCI Insight 7(2022).

12.       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).

13.       Abdul-Sater, A.A., et al. The signaling adaptor TRAF1 negatively regulates Toll-like receptor signaling and this underlies its role in rheumatic disease. Nat. Immunol. 18, 26-35 (2017).

14.       Edilova, M.I., et al. The PKN1- TRAF1 signaling axis as a potential new target for chronic lymphocytic leukemia. Oncoimmunology 10, 1943234 (2021).

Appointments

• 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