TANIA H. WATTS, Ph.D.

T cells, TNFR family members and the balance between immune control and immune pathology during acute and chronic viral infection; Lymphocyte survival and T cell memory

Department of Immunology Medical Sciences Building 1 King's College Circle Toronto, Ontario M5S 1A8 Tel: (416) 978-4551 E-mail: tania.watts@utoronto.ca

1) Tania Watts currently holds the Sanofi Pasteur Chair in Human Immunology

2) Tania Watts is Director of the Toronto Human Immunology Network, a FOCiS Center of Excellence

3) Tania Watts is the Director of the Faculty of Medicine flow cytometry facility

Upon 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. 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 (2-5). 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. In the last few years, studies of chronic viral infection in mice and humans have revealed several inhibitory mechanisms that are induced during chronic viral infection to prevent immune pathology. While it is clear that these inhibitory mechanisms are important, the question remained as to what happens to inducible stimulatory receptors when virus persists. Recently 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.

Another interest of our laboratory is to understand the mechanisms that control the persistence of memory T cells as well as the survival of immune related cancer cells. We have shown that the TNF family ligand 4-1BBL plays a key role in sustaining the survival of memory T cells in the weeks after the virus is cleared (7). Interestingly, incorporating 4-1BBL into an adenovirus vaccine vector can prolong the duration of CD8 T cell mediated protection to influenza virus in mice (8). The signaling adaptor TRAF1 is important for the persistence of activated and memory T cells, at least in part through its affects on decreasing the levels of the proapoptotic molecule BIM (9-11). A current interest therefore, is to understand the role of TRAF1 expression in leukemia and lymphoma.

My laboratory also has a strong interest in T cell immunity to viruses, including HIV and influenza virus, in humans. 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 KLRG1^hiCD57^hi T cell population was a predictor of a poor antibody response to vaccination to seasonal H1N1 influenza (12). We have also examined the state of immunity to A/2009 pandemic influenza in the Toronto population at 1 year post-pandemic.

Our research is currently funded by the Canadian Institutes for Health Research and the Canadian Cancer Society.

1. Watts, T. H. 2005. TNF/TNFR family members in costimulation of T cell responses. Ann. Rev. Immunol. 23:23-68.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. Pulle, G., M. Vidric, and T. H. Watts. 2006. IL-15-dependent induction of 4-1BB promotes antigen-independent CD8 memory T cell survival. J. Immunol. 176:2739-2748.
8. Moraes, T. J., G. H. Lin, T. Wen, and T. H. Watts. 2011. Incorporation of 4-1BB ligand into an adenovirus vaccine vector increases the number of functional antigen-specific CD8 T cells and enhances the duration of protection against influenza-induced respiratory disease. Vaccine 29:6301-6312.
9. 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.
10. Sabbagh, L., G. Pulle, Y. Liu, E. N. Tsitsikov, and T. H. Watts. 2008. ERK-Dependent Bim Modulation Downstream of the 4-1BB-TRAF1 Signaling Axis Is a Critical Mediator of CD8 T Cell Survival In Vivo. J. Immunol. 180:8093-8101.
11. 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.
12. 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.

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