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    Liisa K Selin MD, PhD

    TitleProfessor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentPathology
    AddressUniversity of Massachusetts Medical School
    55 Lake Avenue North
    Worcester MA 01655
    Phone508-856-3039
      Other Positions
      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentImmunology and Virology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentMD/PhD Program

      InstitutionUMMS - Programs, Centers and Institutes
      DepartmentCenter for AIDS Research

        Overview 
        Narrative

        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.

        Liisa_Selin

        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)-M158-66 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.



        Rotation Projects

        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.


        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Prince AL, Watkin LB, Yin CC, Selin LK, Kang J, Schwartzberg PL, Berg LJ. Innate PLZF+CD4+ aß T Cells Develop and Expand in the Absence of Itk. J Immunol. 2014 Jul 15; 193(2):673-87.
          View in: PubMed
        2. Cornberg M, Kenney LL, Chen AT, Waggoner SN, Kim SK, Dienes HP, Welsh RM, Selin LK. Clonal exhaustion as a mechanism to protect against severe immunopathology and death from an overwhelming CD8 T cell response. Front Immunol. 2013; 4:475.
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        3. Kraft AR, Wlodarczyk MF, Kenney LL, Selin LK. PC61 (Anti-CD25) Treatment Inhibits Influenza A Virus-Expanded Regulatory T Cells and Severe Lung Pathology during a Subsequent Heterologous Lymphocytic Choriomeningitis Virus Infection. J Virol. 2013 Dec; 87(23):12636-47.
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        4. Benn CS, Netea MG, Selin LK, Aaby P. A small jab - a big effect: nonspecific immunomodulation by vaccines. Trends Immunol. 2013 Sep; 34(9):431-9.
          View in: PubMed
        5. Wlodarczyk MF, Kraft AR, Chen HD, Kenney LL, Selin LK. Anti-IFN-? and peptide-tolerization therapies inhibit acute lung injury induced by cross-reactive influenza A-specific memory T cells. J Immunol. 2013 Mar 15; 190(6):2736-46.
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        6. Chen AT, Cornberg M, Gras S, Guillonneau C, Rossjohn J, Trees A, Emonet S, de la Torre JC, Welsh RM, Selin LK. Loss of anti-viral immunity by infection with a virus encoding a cross-reactive pathogenic epitope. PLoS Pathog. 2012; 8(4):e1002633.
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        7. Waggoner SN, Cornberg M, Selin LK, Welsh RM. Natural killer cells act as rheostats modulating antiviral T cells. Nature. 2012 Jan 19; 481(7381):394-8.
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        8. Flanagan KL, Klein SL, Skakkebaek NE, Marriott I, Marchant A, Selin L, Fish EN, Prentice AM, Whittle H, Benn CS, Aaby P. Sex differences in the vaccine-specific and non-targeted effects of vaccines. Vaccine. 2011 Mar 16; 29(13):2349-54.
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        9. Calcagno C, Puzone R, Pearson YE, Cheng Y, Ghersi D, Selin LK, Welsh RM, Celada F. Computer simulations of heterologous immunity: highlights of an interdisciplinary cooperation. Autoimmunity. 2011 Jun; 44(4):304-14.
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        10. Selin LK, Wlodarczyk MF, Kraft AR, Nie S, Kenney LL, Puzone R, Celada F. Heterologous immunity: immunopathology, autoimmunity and protection during viral infections. Autoimmunity. 2011 Jun; 44(4):328-47.
          View in: PubMed
        11. Pearson YE, Cheng Y, Selin LK, Puzone R, Celada F. Systematic simulation of cross-reactivity predicts ambiguity in Tk memory: it may save lives of the infected, but limits specificities vital for further responses. Autoimmunity. 2011 Jun; 44(4):315-27.
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        12. Tirabassi RS, Ace CI, Levchenko T, Torchilin VP, Selin LK, Nie S, Guberski DL, Yang K. A mucosal vaccination approach for herpes simplex virus type 2. Vaccine. 2011 Jan 29; 29(5):1090-8.
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        13. Clute SC, Naumov YN, Watkin LB, Aslan N, Sullivan JL, Thorley-Lawson DA, Luzuriaga K, Welsh RM, Puzone R, Celada F, Selin LK. Broad cross-reactive TCR repertoires recognizing dissimilar Epstein-Barr and influenza A virus epitopes. J Immunol. 2010 Dec 1; 185(11):6753-64.
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        14. Shen ZT, Brehm MA, Daniels KA, Sigalov AB, Selin LK, Welsh RM, Stern LJ. Bi-specific MHC heterodimers for characterization of cross-reactive T cells. J Biol Chem. 2010 Oct 22; 285(43):33144-53.
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        15. Welsh RM, Che JW, Brehm MA, Selin LK. Heterologous immunity between viruses. Immunol Rev. 2010 May; 235(1):244-66.
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        16. Nie S, Lin SJ, Kim SK, Welsh RM, Selin LK. Pathological features of heterologous immunity are regulated by the private specificities of the immune repertoire. Am J Pathol. 2010 May; 176(5):2107-12.
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        17. Cornberg M, Clute SC, Watkin LB, Saccoccio FM, Kim SK, Naumov YN, Brehm MA, Aslan N, Welsh RM, Selin LK. CD8 T cell cross-reactivity networks mediate heterologous immunity in human EBV and murine vaccinia virus infections. J Immunol. 2010 Mar 15; 184(6):2825-38.
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        18. Nie S, Cornberg M, Selin LK. Resistance to vaccinia virus is less dependent on TNF under conditions of heterologous immunity. J Immunol. 2009 Nov 15; 183(10):6554-60.
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        19. Munitic I, Decaluwe H, Evaristo C, Lemos S, Wlodarczyk M, Worth A, Le Bon A, Selin LK, Rivière Y, Di Santo JP, Borrow P, Rocha B. Epitope specificity and relative clonal abundance do not affect CD8 differentiation patterns during lymphocytic choriomeningitis virus infection. J Virol. 2009 Nov; 83(22):11795-807.
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        20. Welsh RM, Selin LK. Attrition of memory CD8 T cells. Nature. 2009 Jun 4; 459(7247):E3-4; discussion E4.
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        21. Cheng Y, Ghersi D, Calcagno C, Selin LK, Puzone R, Celada F. A discrete computer model of the immune system reveals competitive interactions between the humoral and cellular branch and between cross-reacting memory and naïve responses. Vaccine. 2009 Feb 5; 27(6):833-45.
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        22. Naumov YN, Naumova EN, Yassai MB, Kota K, Welsh RM, Selin LK. Multiple glycines in TCR alpha-chains determine clonally diverse nature of human T cell memory to influenza A virus. J Immunol. 2008 Nov 15; 181(10):7407-19.
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        23. Yang K, Whalen BJ, Tirabassi RS, Selin LK, Levchenko TS, Torchilin VP, Kislauskis EH, Guberski DL. A DNA vaccine prime followed by a liposome-encapsulated protein boost confers enhanced mucosal immune responses and protection. J Immunol. 2008 May 1; 180(9):6159-67.
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        24. Selin LK, Brehm MA. Frontiers in nephrology: heterologous immunity, T cell cross-reactivity, and alloreactivity. J Am Soc Nephrol. 2007 Aug; 18(8):2268-77.
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        25. Cornberg M, Sheridan BS, Saccoccio FM, Brehm MA, Selin LK. Protection against vaccinia virus challenge by CD8 memory T cells resolved by molecular mimicry. J Virol. 2007 Jan; 81(2):934-44.
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        26. Naumov YN, Naumova EN, Clute SC, Watkin LB, Kota K, Gorski J, Selin LK. Complex T cell memory repertoires participate in recall responses at extremes of antigenic load. J Immunol. 2006 Aug 1; 177(3):2006-14.
          View in: PubMed
        27. Selin LK, Brehm MA, Naumov YN, Cornberg M, Kim SK, Clute SC, Welsh RM. Memory of mice and men: CD8+ T-cell cross-reactivity and heterologous immunity. Immunol Rev. 2006 Jun; 211:164-81.
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        28. Cornberg M, Chen AT, Wilkinson LA, Brehm MA, Kim SK, Calcagno C, Ghersi D, Puzone R, Celada F, Welsh RM, Selin LK. Narrowed TCR repertoire and viral escape as a consequence of heterologous immunity. J Clin Invest. 2006 May; 116(5):1443-56.
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        29. Bahl K, Kim SK, Calcagno C, Ghersi D, Puzone R, Celada F, Selin LK, Welsh RM. IFN-induced attrition of CD8 T cells in the presence or absence of cognate antigen during the early stages of viral infections. J Immunol. 2006 Apr 1; 176(7):4284-95.
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        30. Welsh RM, Kim SK, Cornberg M, Clute SC, Selin LK, Naumov YN. The privacy of T cell memory to viruses. Curr Top Microbiol Immunol. 2006; 311:117-53.
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        31. Clute SC, Watkin LB, Cornberg M, Naumov YN, Sullivan JL, Luzuriaga K, Welsh RM, Selin LK. Cross-reactive influenza virus-specific CD8+ T cells contribute to lymphoproliferation in Epstein-Barr virus-associated infectious mononucleosis. J Clin Invest. 2005 Dec; 115(12):3602-12.
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        32. Kim SK, Cornberg M, Wang XZ, Chen HD, Selin LK, Welsh RM. Private specificities of CD8 T cell responses control patterns of heterologous immunity. J Exp Med. 2005 Feb 21; 201(4):523-33.
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        33. Selin LK, Cornberg M, Brehm MA, Kim SK, Calcagno C, Ghersi D, Puzone R, Celada F, Welsh RM. CD8 memory T cells: cross-reactivity and heterologous immunity. Semin Immunol. 2004 Oct; 16(5):335-47.
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        34. Brehm MA, Selin LK, Welsh RM. CD8 T cell responses to viral infections in sequence. Cell Microbiol. 2004 May; 6(5):411-21.
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        35. Selin LK, Cornberg M. Embedding T cells in the matrix. Nat Med. 2004 Apr; 10(4):343-5.
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        36. Welsh RM, Selin LK, Szomolanyi-Tsuda E. Immunological memory to viral infections. Annu Rev Immunol. 2004; 22:711-43.
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        37. Selin LK, Welsh RM. Plasticity of T cell memory responses to viruses. Immunity. 2004 Jan; 20(1):5-16.
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        38. Chen HD, Fraire AE, Joris I, Welsh RM, Selin LK. Specific history of heterologous virus infections determines anti-viral immunity and immunopathology in the lung. Am J Pathol. 2003 Oct; 163(4):1341-55.
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        39. Wang XZ, Stepp SE, Brehm MA, Chen HD, Selin LK, Welsh RM. Virus-specific CD8 T cells in peripheral tissues are more resistant to apoptosis than those in lymphoid organs. Immunity. 2003 May; 18(5):631-42.
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        40. Naumov YN, Naumova EN, Hogan KT, Selin LK, Gorski J. A fractal clonotype distribution in the CD8+ memory T cell repertoire could optimize potential for immune responses. J Immunol. 2003 Apr 15; 170(8):3994-4001.
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        41. Kim SK, Brehm MA, Welsh RM, Selin LK. Dynamics of memory T cell proliferation under conditions of heterologous immunity and bystander stimulation. J Immunol. 2002 Jul 1; 169(1):90-8.
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        42. Brehm MA, Pinto AK, Daniels KA, Schneck JP, Welsh RM, Selin LK. T cell immunodominance and maintenance of memory regulated by unexpectedly cross-reactive pathogens. Nat Immunol. 2002 Jul; 3(7):627-34.
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        43. Welsh RM, Selin LK. No one is naive: the significance of heterologous T-cell immunity. Nat Rev Immunol. 2002 Jun; 2(6):417-26.
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        44. Selin LK, Brehm MA, Kim SK, Chen HD. Heterologous immunity and the CD8 T cell network. Springer Semin Immunopathol. 2002; 24(2):149-68.
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        45. Chen HD, Fraire AE, Joris I, Brehm MA, Welsh RM, Selin LK. Memory CD8+ T cells in heterologous antiviral immunity and immunopathology in the lung. Nat Immunol. 2001 Nov; 2(11):1067-76.
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        46. Selin LK, Santolucito PA, Pinto AK, Szomolanyi-Tsuda E, Welsh RM. Innate immunity to viruses: control of vaccinia virus infection by gamma delta T cells. J Immunol. 2001 Jun 1; 166(11):6784-94.
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        47. Varga SM, Selin LK, Welsh RM. Independent regulation of lymphocytic choriomeningitis virus-specific T cell memory pools: relative stability of CD4 memory under conditions of CD8 memory T cell loss. J Immunol. 2001 Feb 1; 166(3):1554-61.
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        48. Lin MY, Selin LK, Welsh RM. Evolution of the CD8 T-cell repertoire during infections. Microbes Infect. 2000 Jul; 2(9):1025-39.
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        49. Welsh RM, McNally JM, Brehm MA, Selin LK. Consequences of cross-reactive and bystander CTL responses during viral infections. Virology. 2000 Apr 25; 270(1):4-8.
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        50. Selin LK, Lin MY, Kraemer KA, Pardoll DM, Schneck JP, Varga SM, Santolucito PA, Pinto AK, Welsh RM. Attrition of T cell memory: selective loss of LCMV epitope-specific memory CD8 T cells following infections with heterologous viruses. Immunity. 1999 Dec; 11(6):733-42.
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        51. Selin LK, Varga SM, Wong IC, Welsh RM. Protective heterologous antiviral immunity and enhanced immunopathogenesis mediated by memory T cell populations. J Exp Med. 1998 Nov 2; 188(9):1705-15.
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        52. Welsh RM, Lin MY, Lohman BL, Varga SM, Zarozinski CC, Selin LK. Alpha beta and gamma delta T-cell networks and their roles in natural resistance to viral infections. Immunol Rev. 1997 Oct; 159:79-93.
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        53. Selin LK, Welsh RM. Cytolytically active memory CTL present in lymphocytic choriomeningitis virus-immune mice after clearance of virus infection. J Immunol. 1997 Jun 1; 158(11):5366-73.
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        54. Selin LK, Vergilis K, Welsh RM, Nahill SR. Reduction of otherwise remarkably stable virus-specific cytotoxic T lymphocyte memory by heterologous viral infections. J Exp Med. 1996 Jun 1; 183(6):2489-99.
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        55. Welsh RM, Selin LK, Razvi ES. Role of apoptosis in the regulation of virus-induced T cell responses, immune suppression, and memory. J Cell Biochem. 1995 Oct; 59(2):135-42.
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        56. Zarozinski CC, Fynan EF, Selin LK, Robinson HL, Welsh RM. Protective CTL-dependent immunity and enhanced immunopathology in mice immunized by particle bombardment with DNA encoding an internal virion protein. J Immunol. 1995 Apr 15; 154(8):4010-7.
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        57. Selin LK, Welsh RM. Specificity and editing by apoptosis of virus-induced cytotoxic T lymphocytes. Curr Opin Immunol. 1994 Aug; 6(4):553-9.
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        58. Selin LK, Nahill SR, Welsh RM. Cross-reactivities in memory cytotoxic T lymphocyte recognition of heterologous viruses. J Exp Med. 1994 Jun 1; 179(6):1933-43.
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        59. Wilkins J, Selin L, Stewart S, Sivananthan K, Stupack D. The interactions of gamma delta T cells with extracellular matrix: receptor expression and utilization patterns. Scand J Immunol. 1992 Aug; 36(2):213-9.
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        60. Selin LK, Stewart S, Shen C, Mao HQ, Wilkins JA. Reactivity of gamma delta T cells induced by the tumour cell line RPMI 8226: functional heterogeneity of clonal populations and role of GroEL heat shock proteins. Scand J Immunol. 1992 Jul; 36(1):107-17.
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        61. Freedman MS, Ruijs TC, Selin LK, Antel JP. Peripheral blood gamma-delta T cells lyse fresh human brain-derived oligodendrocytes. Ann Neurol. 1991 Dec; 30(6):794-800.
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        62. Selin LK, Hammond GW, Aoki FY. Neonatal herpes simplex virus infection in Manitoba, 1980 to 1986, and implications for preventive strategies. Pediatr Infect Dis J. 1988 Oct; 7(10):733-4.
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