Section: Research

Liisa Selin, M.D., Ph.D.

Academic Role: Professor

Faculty Appointment(s) In:
   Pathology

Other Affiliation(s):
   Center for AIDS Research
   Program in Immunology and Virology

Mechanisms of viral immunology: heterologous immunity and CD8 T cell crossreactivity during viral infections.

 A comprehensive understanding of the mechanisms associated with the generation and modulation of immunological T cell memory will lead to a better understanding of how the immune system controls viral infections but also causes immune-mediated pathology. Our studies with viruses in murine systems have focused on virus-specific memory T cell populations, which demonstrate plasticity in antigen recognition and in their ability to accommodate new memory T cell populations. Memory T cells laid down as a consequence of one infection can influence protective immunity and immunopathology associated with a second unrelated virus. We have referred to this phenomenon as T cell-dependent heterologous immunity and immunopathology. The focus of our work is to develop a better understanding of the mechanisms associated with the induction of heterologous immunity, specifically the role cross-reactive memory T cell responses and cytokines play in decreasing or augmenting viral replication and altering immunopathology. We have identified a matrix of cross-reactive epitopes between viruses, and developed both systemic and respiratory infection model systems. We use several virus systems, but focus on lymphocytic chorimeningitis (LCMV) and Pichinde (PV) viruses, distantly related arenaviruses whose T cell responses are well defined, and on the poxvirus vaccinia (VV), which is used as a vaccine for smallpox and as a recombinant vaccine and vector for many antigens.

Our studies in human viral infections on heterologous immunity and cross-reactive T cell responses during Epstein Barr virus (EBV) infection only begin to scratch the surface of the prevalence and potential impact of cross-reactive T cell responses on both vaccine development and immunopathology.   There is very little understanding of the structural and functional interaction of one TCR with two different ligands. We have identified directly ex vivo and in bulk T cell cultures HLA-A2-restricted cross-reactive CD8 T cell responses that recognize both EBV BMLF-1 and influenza A M1 HLA-A2 restricted epitopes. These cross-reactive T cells were found to participate in acute infectious mononucleosis (IM). Five of 8 young adult HLA-A2+ patients experiencing IM had an increased number of influenza virus (FLU)-M1_58-66 specific CD8+ T cells in their peripheral blood as compared to healthy donors.   Two of 5 IM patients with augmented FLU-M1 responses had high levels of tetramer-defined cross-reactive cells as measured directly ex vivo in their peripheral blood.  EBV likely activates multiple populations of cross-reactive memory cells involved in the development of IM, and we have been able to provide evidence that those specific to FLU-M1 can contribute to this phenomenon. In order to better understand how cross-reactive CD8 T cells may be modulating disease outcome by enhancing viral clearance or inducing immunopathology, such as that seen in IM, we continue to characterize the cross-reactive TCR, both functionally and structurally, and examine how cross-reactivity influences the evolution of antigen-specific TCR repertoire development and disease outcome in both mice and humans during viral infections.

Office: S2-238
Phone: 508-856-3039
Fax: 508-856-5780
E-mail: Liisa.Selin@umassmed.edu
Keywords: Immunology, T lymphocytes, Viral Pathogenesis, Heterologous, Viral Infections and Immunity

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