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.

Representative Publications:

S.C. Clute, L.B. Watkin, M. Cornberg, Y. N. Naumov, J.L. Sullivan, K. Luzuriaga, R.M. Welsh and L.K. Selin. Cross-reactive influenza virus-specific CD8 T cells contribute to the lymphoproliferation in Epstein-Barr virus-associated infectious mononucleosis.(2005) (in press Journal of Clinical Investigation).

S.K. Kim, X.Z. Wang, M. Cornberg, H.D. Chen, L.K. Selin.and R.M. Welsh. 2005. Private specificities of CD8 T cell responses control patterns of heterologous immunity. J. Exp. Med. 201:523-33.

L.K. Selin, M. Cornberg, M.A. Brehm, S.K. Kim, and R.M. Welsh. 2004. CD8 memory T cells: cross-reactivity and heterologous immunity. Sem. Immunol. 16:335-347. (Review).

L.K. Selin & M. Cornberg. 2004 Embedding T cells in the matrix. Nature Medicine (News and Views) 10:343-345.

L.K.Selin 2004 Lymphocyte effector functions memory and unique subsets of lymphocytes. (editorial overview). Curr. Opin. Immunol. 16: 257-258.

L.K. Selin and R.M. Welsh. 2004 Plasticity of T cell memory responses to viruses. Immunity Jan:20(1):5-16. (Review).

R.M. Welsh, L.K. Selin and E. Szomolanyi-Tsuda. 2004 Immunological memory to viral infections. Ann. Rev. Immunol. Vol. 22, Page 711-743. (Review)

H.D. Chen, A.E. Fraire, I. Joris, R.M. Welsh and L.K. Selin 2003. Specific history of heterologous virus infections determines antiviral immunity and immunopathology in the lung. Amer. J. Path 163: 1341-55.

X.Z. Wang, S.E. Stepp, M.A. Brehm, H.D.Chen, L.K.Selin and R.M. Welsh. 2003. Virus-specific CD8 T cells in peripheral tissues are more resistant to apoptosis than those in lymphoid organs. Immunity, 18:631-642.

Y.N. Naumov, E.N. Naumov, K.T. Hogan, L.K. Selin and J. Gorski. 2003. A fractal clonotype distribution in the CD8 memory T-cell repertoire allows for optimized antigen recognition. J. Immunol. 170:3994-4001.

R.M. Welsh & L.K. Selin. No one is naïve: the significance of heterologous T cell immunity. 2002.  Nature Rev. Immunol. 2: 417-426. (Review)

S.K. Kim, M.A. Brehm, R.M. Welsh and L.K. Selin. 2002 Dynamics of CD8 T cell proliferation under conditions of heterologous immunity and bystander stimulation. J. Immunol 169:90-98.

M.A. Brehm, A.K. Pinto, K.A. Daniels, J.P. Schneck, R.M. Welsh, and L.K. Selin. 2002. T cell immunodominance and maintenance of memory regulated by unexpectedly cross-reactive pathogens.  Nature Immunol. 3:627-34.

H..D. Chen, A.E. Fraire, I. Joris, M.A. Brehm, R.M. Welsh and L.K. Selin. 2001. Memory CD8+ T Cells in heterologous antiviral immunity and immunopathology in the lung. Nature Immunol. 2:1067-1076.

L.K. Selin, M.Y. Lin, K.A. Kraemer, D. Pardoll, J.P. Schneck, S.M. Varga, P. Santolucito, A.K. Pinto and R.M. Welsh. 1999. Attrition of T cell memory: selective loss of lymphocytic choriomeningitis virus (LCMV) epitope-specific memory CD8 T cells following infections with heterologous viruses. Immunity 11:733-742.

Rotation Projects for graduate students:

1. Examining the role of cross-reactive CD8 memory T cells in mediating the EBV-induced infectious mononucleosis syndrome in humans.
2. Examining the role of cross-reactive CD8 memory T cells and cytokines in murine models of viral infection. Examining the mechanisms used by these memory T cells to unrelated infections to modulate disease outcome either for the bad or the good.

Academic Background

Dr. Liisa K. Selin received her B.Sc. degree (Biology and Psychology) in 1974 and M.D. degree in 1979, both from Dalhousie University, Halifax, Nova Scotia.  She is Board Certified in Internal Medicine (1984, in Canada ), with fellowship training in infectious diseases.  She also completed her PhD training in microbiology and immunology at the University of Manitoba, Winnipeg, Manitoba (Canada) in 1993 followed by 2 years of postdoctoral training at the University of Massachusetts Medical School, Worcester, MA.  She joined the faculty in the Dept. of Pathology at the University of Massachusetts Medical School as an Instructor in 1994 and was promoted to her present position as Associate Professor in 2001.  Dr. Selin has studied the role of T cells in response to viral infections; specifically, initially identifying and focusing on the phenomenon of heterologous immunity, whereby memory T cell responses to pathogens can influence the outcome to subsequent infection with unrelated pathogens. The effects of heterologous immunity are now known, at least in part, to be mediated by cross-reactive T cell responses and mediate both protective effects, immune enhancement and can induce immunopathology.  In the past decade she has published and spoken on numerous aspects of the heterologous immunity and CD8 T cell cross-reactivity. 

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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