Man and other vertebrates have evolved innate and adaptive host response mechanisms to clear viral infections and provide permanent resistance thereafter. Among the most important weapons against these pathogens are cytotoxic lymphocytes that can lyse virus-infected cells and secrete anti-viral cytokines such as interferon (IFN)g. These include natural killer (NK) cells and T cells expressing either gamma sigma or alpha beta T cell receptors (TCR). My laboratory originally showed that NK cells in mice become activated during infections and clear viruses such as murine cytomegalovirus (MCMV), an important model for human CMV. We report here progress showing that gammas T cells become activated and control infections with vaccinia virus (VV), which is used for human small pox vaccination. We also describe the new phenomenon of heterologous T cell-dependent natural immunity, whereby subpopulations of memory T cells specific for one virus become activated and alter the pathogenesis of putatively unrelated viruses early in infection. The functions of these cytotoxic lymphocytes are regulated by membrane receptor molecules. """"""""NK receptors"""""""" (NKR) are on most NK cells and some T cells, and we report here that they are expressed on many virus-induced gamma sigma T cells and on distinct subpopulations of conventional virus-specific alphabeta T cells of the memory phenotype. Here, we propose to continue our integrated studies examining innate and adaptive immunity to viral infections and the contributions of NXR to the different classes of cytotoxic lymphocytes that regulate these infections. We will (1) examine the role of NKR on alphabeta T cell repertoire development during viral infection, (2) examine the activation and antiviral activity of gamma T cells during VV infection, (3) evaluate the role of negative signalling by NKR in the control of infections by T cells and NK cells, and (4) examine redundancies, synergisms, and antagonisms of NK, gamma sigma T, and memory alphabeta T cell responses to viruses. This work should clarify how these effector systems act and interact to rid the host of infectious agents and tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA034461-22
Application #
6843160
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Howcroft, Thomas K
Project Start
1983-05-01
Project End
2006-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
22
Fiscal Year
2005
Total Cost
$268,710
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Pathology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Waggoner, Stephen N; Daniels, Keith A; Welsh, Raymond M (2014) Therapeutic depletion of natural killer cells controls persistent infection. J Virol 88:1953-60
Mishra, Rabinarayan; Welsh, Raymond; Szomolanyi-Tsuda, Eva (2014) NK cells and virus-related cancers. Crit Rev Oncog 19:107-19
Rodriguez, Idalia A; Welsh, Raymond M (2013) Possible role of a cell surface carbohydrate in evolution of resistance to viral infections in old world primates. J Virol 87:8317-26
Welsh, Raymond M; Waggoner, Stephen N (2013) NK cells controlling virus-specific T cells: Rheostats for acute vs. persistent infections. Virology 435:37-45
Cornberg, Markus; Kenney, Laurie L; Chen, Alex T et al. (2013) Clonal exhaustion as a mechanism to protect against severe immunopathology and death from an overwhelming CD8 T cell response. Front Immunol 4:475
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
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
Mishra, Rabinarayan; Chen, Alex T; Welsh, Raymond M et al. (2010) NK cells and gammadelta T cells mediate resistance to polyomavirus-induced tumors. PLoS Pathog 6:e1000924
Rathinam, Vijay A K; Jiang, Zhaozhao; Waggoner, Stephen N et al. (2010) The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nat Immunol 11:395-402
Mathurin, Keisha S; Martens, Gregory W; Kornfeld, Hardy et al. (2009) CD4 T-cell-mediated heterologous immunity between mycobacteria and poxviruses. J Virol 83:3528-39

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