Viruses, including HIV, EBV, and CMV, are potent inducers of T cell responses, resulting in hyperplasia of lymphoid organs and the generation of high levels of CD8+ cytotoxic T lymphocytes (CTL). We have found, using mice infected with lymphocytic choriomeningitis virus (LCMV), that the massive T cell response is primarily virus-specific, with little indication of """"""""bystander proliferation"""""""" of T cells lacking specificity for the virus. However, we have shown that n:any of the virus-induced T cells have dual specificity and often recognize targets in addition to the virus-infected syngeneic targets that are stimulating them. These include uninfected allogeneic targets and syngeneic targets infected with putatively unrelated heterologous viruses. The T cell repertoire remains substantially skewed with virus-specific T cells long after clearance of a virus infection, and the introduction of another virus into this skewed repertoire results in the expansion of many T cells crossreactive between the two viruses. Subsequent to the second infection there is a quantitative reduction and qualitative alteration of T cell memory to the first virus after the immune system reaches homeostasis. Our analyses have indicated that T cells exist as a network of cells continually being modulated by crossreactive stimulations and apoptotic deletions, and that how one responds to a virus infection will depend on one's history of exposure to putatively unrelated antigens. The purpose of this grant is to examine the roles of crossreactive T cells vs. bystander events during viral infections by: (1) analyzing the evolution of the T cell repertoire during viral infections; (2) defining the specificity of crossreactive CTL responses between LCMV and other viruses, including Pichinde virus; (3) determining whether bystander events contribute to cytolytic activation or T cell accumulation; (4) determining how the T cell repertoire and pre-existing memory pool is modulated as a consequence of heterologous infections; and (5) examining the role of crossreactive T cells in viral pathogenesis and allograft rejection.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Special Emphasis Panel (ZRG5-EVR (04))
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Serrate-Sztein, Susana
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University of Massachusetts Medical School Worcester
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Waggoner, Stephen N; Cornberg, Markus; Selin, Liisa K et al. (2012) Natural killer cells act as rheostats modulating antiviral T cells. Nature 481:394-8
Selin, Liisa K; Wlodarczyk, Myriam F; Kraft, Anke R et al. (2011) Heterologous immunity: immunopathology, autoimmunity and protection during viral infections. Autoimmunity 44:328-47
Waggoner, Stephen N; Taniguchi, Ruth T; Mathew, Porunelloor A et al. (2010) Absence of mouse 2B4 promotes NK cell-mediated killing of activated CD8+ T cells, leading to prolonged viral persistence and altered pathogenesis. J Clin Invest 120:1925-38
Kang, Yoon-Joong; Wang, Xiaosong; Lin, Sue-Jane et al. (2010) An active CD8alpha/pMHCI interaction is required for CD8 single positive thymocyte differentiation. Eur J Immunol 40:836-48
Welsh, Raymond M; Che, Jenny W; Brehm, Michael A et al. (2010) Heterologous immunity between viruses. Immunol Rev 235:244-66
Brehm, M A; Daniels, K A; Priyadharshini, B et al. (2010) Allografts stimulate cross-reactive virus-specific memory CD8 T cells with private specificity. Am J Transplant 10:1738-48
Nie, Siwei; Lin, Sue-Jane; Kim, Sung-kwon et al. (2010) Pathological features of heterologous immunity are regulated by the private specificities of the immune repertoire. Am J Pathol 176:2107-12
Cornberg, Markus; Clute, Shalyn C; Watkin, Levi B et al. (2010) CD8 T cell cross-reactivity networks mediate heterologous immunity in human EBV and murine vaccinia virus infections. J Immunol 184:2825-38
Mangada, Julie; Pearson, Todd; Brehm, Michael A et al. (2009) Idd loci synergize to prolong islet allograft survival induced by costimulation blockade in NOD mice. Diabetes 58:165-73
Seedhom, Mina O; Jellison, Evan R; Daniels, Keith A et al. (2009) High frequencies of virus-specific CD8+ T-cell precursors. J Virol 83:12907-16

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