- 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. 10.1111/j.1600-065X.2011.01063.x
- Clouthier DL, Watts TH. TNFRs and Control of Chronic LCMV Infection: Implications for Therapy. Trends Immunol 2015, 36(11): 697-708. 10.1016/j.it.2015.09.005
- Chang YH, Wang KC, Chu KL, Clouthier DL, Tran AT, Torres Perez MS, Zhou AC, Abdul-Sater AA, Watts TH. Dichotomous Expression of TNF Superfamily Ligands on Antigen-Presenting Cells Controls Post-priming Anti-viral CD4(+) T Cell Immunity. Immunity 2017, 47(5): 943-958 e949. 10.1016/j.immuni.2017.10.014
- Girard M, Law JC, Edilova MI, Watts TH. Type I interferons drive the maturation of human DC3s with a distinct costimulatory profile characterized by high GITRL. Sci Immunol 2020, 5(53). 10.1126/sciimmunol.abe0347
Full text: http://immunology.sciencemag.org/cgi/content/full/5/53/eabe0347?ijkey=i1yPaF.5yf0ZA&keytype=ref&siteid=immunology
- 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. 10.1038/mi.201124
Chu KL, Batista NV, Wang KC, Zhou AC, Watts TH. 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 2019, 12(2): 363-377. 10.1038/s41385-018-0105-5
Zhou AC, Batista NV, Watts TH. 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 2019, 202(8): 2482-2492. 10.4049/jimmunol.1800795
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. 10.1371/journal.pone.0023698
Wagar LE, Rosella L, Crowcroft N, Lowcock B, Drohomyrecky PC, Foisy J, Gubbay J, Rebbapragada A, Winter AL, Achonu C, Ward BJ, 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. 1371/journal.pone.0028063
Law JC, Koh WH, Budylowski P, Lin J, Yue F, Abe KT, Rathod B, Girard M, Li Z, Rini JM, Mubareka S, McGeer A, Chan AK, Gingras AC, Watts TH, M AO. Systematic Examination of Antigen-Specific Recall T Cell Responses to SARS-CoV-2 versus Influenza Virus Reveals a Distinct Inflammatory Profile. J Immunol 2021,206(1): 37-50. 10.4049/jimmunol.2001067
Law JC, Chao GYC, Ward LA, Isho B, Rathod B, Colwill K, Li Z, Rini JM, Yue FY, Mubareka S, McGeer AJ, Ostrowski MA, Gommerman JL, GIngras AC, Watts TH. Immunity to SARS-CoV-2 persists 9 months post-symptoms with an altered T cell phenotype compared to influenza A virus-specific memory. MedRXIV 2021. doi: https://doi.org/10.1101/2021.06.08.21258518
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 COVID19 (11) 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)
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Our research is funded by a Canadian Institutes for Health Foundation Grant, as well as funding from CIHR and the Canadian Immunity task force for COVID19 and a donation from the Speck family.