Heterologous immunity occurring as a consequence of T cell cross-reactivity between unrelated pathogens has been shown by us in animal models to contribute to either enhanced or reduced viral loads and remarkably altered immunopathology against vaccinia virus, arenaviruses, influenza virus, and cytomegalovirus. Examples of such heterologous immunity have now been reported in human infections with Epstein-Barr (by us), dengue and hepatitis C viruses. The overall objective of this grant is to exploit our developed mouse models to determine how T cell frequencies, functions, and repertoires change as the host undergoes successive acute or persistent infections with non-identical viruses, much like that which occurs in humans. Insights on these issues are necessary for the intelligent design of modern vaccines that are effective and without unwanted side effects, as unanticipated T cell cross-reactivity can sometimes lead to damaging pathology. Many issues of heterologous immunity are still unexplored. We know little about how the altered cross-reactive repertoire is formed and how it contributes to immunopathology. We know little about the impact of heterologous immunity as the T cell receptor (TCR) repertoire narrows in the aging host or in hosts rendered lymphopenic by infection, cancer, or immunosuppressive drug treatment. We also lack insight on why heterologous immunity between different pathogens is not necessarily reciprocal. To clarify these issues we propose to examine changes in the TCR repertoire and affinities of cross-reactive T cells under conditions of sequential and persistent viral infections, to examine the MHC basis of heterologous immunity to confirm that it is mediated by TCR-MHC interactions, to examine heterologous immunity under conditions of limited TCR repertoires caused by age or lymphopenia, to determine how frequencies and functions of naive bystander T cells are influenced by infection, and to shed insight on the lack of reciprocity in protective heterologous immunity between pathogens.

Public Health Relevance

Modern vaccine strategies are directed at generating strong memory T cell responses to control viral infections, but memory T cells specific to one virus may cross-react with another and alter its pathogenesis. Understanding the implications of this heterologous immunity in normal and aged hosts should enhance our knowledge of viral pathogenesis and contribute to the design of better vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI081675-27
Application #
8489099
Study Section
Virology - B Study Section (VIRB)
Program Officer
Lapham, Cheryl K
Project Start
1989-06-15
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
27
Fiscal Year
2013
Total Cost
$378,883
Indirect Cost
$148,559
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
Che, Jenny W; Daniels, Keith A; Selin, Liisa K et al. (2017) Heterologous Immunity and Persistent Murine Cytomegalovirus Infection. J Virol 91:
Urban, Stina L; Berg, Leslie J; Welsh, Raymond M (2016) Type 1 interferon licenses naïve CD8 T cells to mediate anti-viral cytotoxicity. Virology 493:52-9
Gil, Anna; Kenney, Laurie L; Mishra, Rabinarayan et al. (2015) Vaccination and heterologous immunity: educating the immune system. Trans R Soc Trop Med Hyg 109:62-9
Che, Jenny W; Kraft, Anke R M; Selin, Liisa K et al. (2015) Regulatory T cells resist virus infection-induced apoptosis. J Virol 89:2112-20
Rydyznski, Carolyn; Daniels, Keith A; Karmele, Erik P et al. (2015) Generation of cellular immune memory and B-cell immunity is impaired by natural killer cells. Nat Commun 6:6375
Che, Jenny W; Selin, Liisa K; Welsh, Raymond M (2015) Evaluation of non-reciprocal heterologous immunity between unrelated viruses. Virology 482:89-97
Daniels, Keith A; Hatfield, Steven D; Welsh, Raymond M et al. (2014) MHC basis of T cell-dependent heterologous immunity to arenaviruses. Virology 464-465:213-217
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
Nayar, Ribhu; Schutten, Elizabeth; Bautista, Bianca et al. (2014) Graded levels of IRF4 regulate CD8+ T cell differentiation and expansion, but not attrition, in response to acute virus infection. J Immunol 192:5881-93

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