Matthew F. Mescher, Ph.D.

Professor
612-626-2368
mesch001@umn.edu

Educational Background

• Hope College, Holland, MI (1970), B.A. (Chemistry)
• Harvard University, Cambridge, MA (1976), Ph.D. (Biochemistry)

Professional Background

• Instructor , Harvard Medical School, Boston, MA, Department of Pathology, 1976 - 1977
• Assistant Professor, Harvard Medical School, Boston, MA, Department of Pathology, 1977 - 1983
• Associate Professor, Harvard Medical School, Boston, MA, Department of Pathology, 1983 - 1985
• Chief and Member, Medical Biology Institute, LaJolla, CA, Division of Membrane Biology, 1985 - 1992
• Professor and Virginia and David C. Utz Land Grant Chair in Fundamental Immunobiology, University of Minnesota Medical School, Minneapolis, MN, Department of Laboratory Medicine and Pathology, 1993 - present
• Professor, University of Minnesota Medical School, Minneapolis MN, Department of Biochemistry, 1994 - present
• Director, University of Minnesota Medical School, Center for Immunology, 1995 - present

Professional Memberships

• The American Association of Immunologists, 1979 - present
• The American Society for Cell Biology, 1980 - present
• The American Chemical Society, 1984 - present
• Member, Allergy and Immunology Study Section, 1990 - 1995

• Virginia and David C. Utz Land Grant Chair in Fundamental Immunobiology

   (endowed chair), 1993 - present

Research Interests

T-Lymphocyte activation; cell-cell interaction and transmembrane signaling. Work in our laboratory focuses on understanding the requirements for activating T-lymphocytes. T-cell activation involves several different receptors on the T-cell interacting with their ligands on the antigen-bearing cell and with cytokines. We are analyzing the contributions of the various receptors to cell-cell adhesion, signal generation and activation of proliferation and differentiation programs using artificial membrane constructs having purified ligands incorporated onto their surfaces. This is allowing us to define the biochemical signaling events (kinase activation, Ca 2+ changes, lipid hydrolysis, etc.) contributed by each receptor and examine the cooperative effects of engaging multiple receptors. In related work, we are using methods of cellular immunology to determine the qualitative and quantitative functional consequences of activating T cells with defined ligands in both in vitro and in vivo model systems. New insights into the requirements for T cell activation gained in these studies are being applied to the development of novel approaches to tumor immunotherapy in both murine models and clinical trials.

Publications

• Kane, K.P. and Mescher, M.F., Antigen recognition by T cells: quantitative effects of augmentation by antibodies providing accessory interactions. J. Immunol. 144:824-829, 1990
• O'Rourke, A.M., Rogers, J. and Mescher, M.F. Activated CD8 binding to class I protein mediated by the T-cell receptor results in signalling. Nature. 346:187-189,1990.
• O'Rourke, A.M., Mescher, M.F. and Webb, S.R. Activation of polyphosphoinositide hydrolysis in T cells by H-2 alloantigen but not MLS determinants. Science. 249:171-174,1990.
• O'Rourke, A.M. and Mescher, M.F. T-cell receptor-activated adhesion systems. Current Opinion in Cell Biology. 2:888-893,1990.
• O'Rourke, A.M., Apgar, J.R., Kane, K.P., Martz, E. and Mescher, M.F. Cytoskeletal function in CD8- and T cell receptor-mediated interaction of cytotoxic T lymphocytes with class I protein. J. Exp. Med. 173: 241-249,1991.
• Heath, W.R., Kane, K.P., Mescher, M.F., and Sherman, L.A. Alloreactive T cells discriminate a diverse set of endogenous peptides. Proc. Natl. Acad. Sci. USA 88:5101-5105,1991.
• Mescher, M.F., O'Rourke, A.M., Champoux, P. and Kane, K.P. Equilibrium binding of cytotoxic T lymphocytes to class I antigen. J. Immunol. 147:36-41,1991.
• Teitell, M., Mescher, M.F., Olson, C.A., Littman, D.R. and Kronenberg, M. The thymus leukemia antigen binds human and mouse CD8. J. Exp. Med. 174:1131-1138,1991.
• Kane, K.P., Sherman, L.A. and Mescher, M.F. Exogenous _2-microglobulin is required for antigenic peptide binding to isolated class I major histocompatibility complex molecules. Eur. J. Immunol. 21:2289-2292,1991.
• Rogers, J. and Mescher, M.F. Augmentation of in vivo cytotoxic T lymphocyte activity and reduction of tumor growth by large multivalent immunogen. J. Immunol. 149:269-276,1992.
• O'Rourke, A.M. and Mescher, M.F. Cytotoxic T-lymphocyte activation involves a cascade of signalling and adhesion events. Nature. 358:253-255,1992.
• Mescher, M.F. Surface contact requirements for activation of cytotoxic T lymphocytes. J. Immunol. 149:2402-2405,1992.
• O'Rourke, A.M. and Mescher, M.F. The roles of CD8 in cytotoxic T lymphocyte function. Immunology Today. 14:183-188,1993.
• Kane, K.P. and Mescher, M.F. Activation of CD8-dependent CTL adhesion and degranulation by peptide class I antigen complexes. J. Immunol. 150:4788-4797,1993.
• O'Rourke, A.M., Ybarrondo, B. and Mescher, M.F. CD8 and antigen-specific T cell adhesion cascades. Sem. in Immunology. 5:263-270,1993.
• Ybarrondo, B., O'Rourke, A.M., Brian, A.A. and Mescher, M.F. Contribution of LFA-1/intercellular adhesion molecule-1 binding to the adhesion/signaling cascade of cytotoxic T lymphocyte activation. J. Exp. Med. 179:359-363, 1994.
• O'Rourke, A.M. and Mescher, M.F. Signals for activation of CD8-dependent adhesion and costimulation in CTLs. J. Immunol. 152:4358-4367, 1994.
• Añel, A., Mescher, M.F. and Kleinfeld, A.M. Activated adhesion of CTL to MHC class I but not fibronectin is inhibited by cis unsaturated fatty acids and PAO. J. Immunol. 155:1039-1046, 1995.
• Mescher, M.F. Molecular interactions in the activation of effector and precursor cytotoxic T lymphocytes. Immunological Reviews. 146:177-210, 1995.
• Mescher, M.F. and Rogers, J.D. Immunotherapy of established murine tumors with large multivalent immunogen and cyclophosphamide.. Immunotherapy. 19(2):102-112, 1996.
• Ni, H.-T., Deeths, M.J. and Mescher, M.F. Phosphatidylinositol 3 kinase activity is not essential for B7-1 mediated costimulation or development of cytotoxicity in murine T cells. J. Immunol. 157:2243-2246, 1996.
• Añel, A., O'Rourke, A.M., Kleinfeld, A.M. and Mescher, M.F. TCR and CD8-dependent tyrosine phosphorylation in cytotoxic T lymphocytes: activation of p56lck by CD8 binding to class I. Eur. J. Immunol. 26:2310-2319, 1996.
• Deeths, M.J. and Mescher, M.F. B7-1 dependent costimulation results in qualitatively and quantitatively different responses by CD4+ and CD8+ T cells. Eur. J. Immunol. 27:598-608, 1997
• Ybarrondo, B., O'Rourke, A.M., McCarthy, J.B. and Mescher, M.F. CTL interaction with fibronectin and vitronectin: activated adhesion and cosignaling. Immunology 91:186-192, 1997.
• Kedl, R.M. and Mescher, M.F. Analysis of adoptively transferred CD8+ TCR transgenic T cells responding to alloantigen in vivo. J. Immunol. 159:650-663, 1997.
• Curtsinger,J., M.J.Deeths, P.Pease and M.F.Mescher. Artificial cell surface constructs for studying receptor-ligand contributions to lymphocyte activation. J. Immunol. Meth. 209:47-57, 1997.
• Curtsinger,J.M., D.C.Lins and M.F.Mescher. CD8+ memory T cells (CD44hi, Ly6C+) are more sensitive than naive cells (CD44lo, Ly6C-) to TCR/CD8 signaling in response to antigen. J. Immunol. 160:3236-3243, 1998
• Kedl,R.M. and Mescher,M.F. Qualitative differences between naive and memory cells make a major contribution to the more rapid and efficient memory CD8+ T cell response. J. Immunol. 161:674-683, 1998.
• Shrikant,P. and Mescher,M.F. Control of syngeneic tumor growth by activation of CD8+ T cells: efficacy is limited by migration away from the site and induction of non-responsiveness. J. Immunol., 162:2858-2866
• Mescher, M.F. and E. Savelieva. Stimulation of tumor-specific immunity using tumor cell plasma membrane antigen. Methods 12:155-164, 1997
• Mescher, M.F. and P.L. Jensen (1999) TCR-initiated adhesion and signaling cascades in CTL activation. In Cytotoxic Cells: Basic Mechanisms and medical Applications (M.V. Sitkovsky and P.A. Henkart, eds) In press
• Curtsinger, J., P. Champoux, D. Lins, F.R. Carbone and M.F. Mescher (1999) Differential regulation of CD8 and LFA-1 adhesion function during T cell differentiation. Submitted for publication.
• Jensen, P., and M.F. Mescher (1999) The role of phosphatidylinositol 3-kinase in TCR signaled activation of CD8-mediated adhesion. Manuscript in preparation.
• Deeths, M.J., and M.F. Mescher (1999) ICAM-1 and B7-1 provide similar but distinct costimulation for CD8+ T cells, while CD4+ T cells are poorly costimulated by ICAM-1. Eur.J. Immunol. 29:45-53.
• Curtsinger,J.M., C.S.Schmidt, A.Mondino, D.C.Lins, R.M.Kedl, M.K.Jenkins and M.F.Mescher. Inflammatory cytokines provide a third signal for activation of naive CD4+ and CD8+ T cells. J. Immunol. 162: 3256-3262.
• Deeths, M.F., R.M. Kedl and Mescher, M.F. (1999) CD8+ T cells become non-responsive (anergic) following activation in the presence of costimulation. J. Immunol. 163: 102-110.
• Shrikant, P., A. Khoruts and M.F. Mescher (1999) CTLA-4 blockade reverses CD8+ T cell tolerance to tumor by a CD4+ T cell and IL-2-dependent mechanism. Immunity 11: 483-493.
• Schmidt, C.S. and Mescher, M.F. (1999) Adjuvant effect of IL-12: conversion of peptide antigen administration from tolerizing to immunizing for CD8+ T cells in vivo. J. Immunol 163: 2561-2567.
• Ni, H.T., J.M. Deeths, W.Li, D.L Mueller and M.F. Mescher. (1999) Signaling pathways activated by leukocyte function-associated Ag-1-dependent costimulation. J. Immunol. 162: 5183-5189
• Shrikant, P. and M.F. Mescher. Tumor therapy using Il-2. Manuscript in preparation
• Shrikant, P. And M.F. Mescher. (2000) Opposing effects of interleukin-2 in tumor immunotherapy: promoting T cell growth and inducting apoptosis. submitted for publication.
• Curtsinger, J.M., J. Valenzuela, D. Lins and M.F. Mescher. Uncoupling proliferation and development of effector function in naive CD8+ T cells: three signals are required for full activation. Submitted for publication.
• Mescher,M.F. and P.L.Jensen (2000) TCR-initiated adhesion and signaling cascades in CTL activation. in Cytotoxic Cells: Basic Mechanisms and Medical Applications, (M.V.Sitkovsky and P.A.Henkart, eds). pp 65-78
• Jensen,P.L. and M.F.Mescher (2001) Role of phosphatidylinositol 3-kinase in TCR-signaled recognition of CD8-mediated adhesion to class I MHC protein. Submitted (in revision).
• Curtsinger,J., P.Champoux, D.Lins, F.R.Carbone and M.Mescher. Differential regulation of CD8 and LFA-1 adhesion function during T cell differentiation. Submitted
• Tham,E.L., P.L.Jensen and M.F.Mescher. (2001) Activation of antigen-specific T cells by artificial constructs having immobilized multimeric peptide-class I complexes and recombinant B7-Fc proteins. J. Immunol. Methods 249:111-119.
• Ni,H.-T., M.J.Deeths and M.F.Mescher (2001) LFA-1-mediated costimulation of CD8+ T cell proliferation requires phosphatidylinositol 3-kinase activity. J. Immunol. 166: 6523-6529
• Tham,E.L., P.Shrikant and Mescher, M.F. Reversal of CD8 T cell 'activation-induced non-responsiveness'. Manuscript in preparation
• Kieper, W.C., Prilic, M., Schmidt, C.S., Mescher, M.F., and Jameson, S.C. IL-12 enhances CD8 T cell homeostatic expansion. J. Immunol, 166:5515-5521, 2001
• Schmidt,C.S. and M.F.Mescher. A third signal is required for in vivo activation of naïve CD8 T cells: a direct link between innate and adaptive immunity. Manuscript in preparation.
• Tham,E.L. and Mescher,M.F. Signaling alterations in activation-induced nonresponsive (AINR) CD8 T cells. J. Immunol. 167: 2040-2048
• Tham,E.L., Shrikant,P. and M.F.Mescher. Activation-induced non-responsiveness (AINR): a Th dependent regulatory checkpoint in the CTL response. J. Immunol. 168: 1190-1197, 2002
• Schmidt,C.S. and M.F.Mescher. IL-12 as a distinct in vivo signal for naïve, but not memory, CD8 T cell activation: direct interaction between innate and adaptive immunity. Manuscript in preparation
• Goldberg,J. and M.F.Mescher. Class I/peptide Ag complexes on microspheres enhance in vivo CD8 T cell responses to tumor. Manuscript in preparation.
• Schmidt,C.S. and M.F.Mescher. Peptide Ag priming of naïve, but not memory, CD8 T cells requires a third signal that can be provided by IL-12. J. Immunol., 168:5521-5529, 2002.
• Shrikant,P. and M.F.Mescher. Opposing effects of interleukin-2 in tumor immunotherapy: promoting CD8 T cell growth and inducing apoptosis. J. Immunol. 169:1753-1759, 2002.
• Tham,E.L. and M.F.Mescher. The post-stimulation program of CD4 versus CD8 T cells (death versus activation-induced non-responsiveness). J. Immunol. 169:1822-1828, 2002.
• Harmala,LAE., Ingulli,E.G., Curtsinger,J.M., Lucido,M.M, Schmidt,C.S. Weigel, B.J., Blazar,B.R., Mescher M.F. and C.A.Pennell, C.A. The adjuvant effects of Mycobacterium tuberculosis heat shock protein 70 result from the rapid and prolonged activation of antigen-specific CD8+ T cells in vivo. J. Immunol. in press.
• Mescher, M.F., J.M.Curtsinger and M.Jenkins. Adjuvants ant the initiation of T cell responses. in Immunological Basis of Vaccine Adjuvants (Hackett,C. and D.Harn, eds), Humana Press, Inc., Totowa, New Jersey. in press.
• Goldberg,J., P.Shrikant, M.F.Mescher. In vivo augmentation of tumor-specific CTL responses by class I/peptide antigen complexes on microspheres (Large Multivalent Immunogen). J. Immunol. 170: 228-235, 2003.
• Valenzuela,J., C.Schmidt and M.F.Mescher. The roles of IL-12 in providing a third signal for clonal expansion of naïve CD8 T cells. J. Immunol. in revision.
• Curtsinger,J. and M.F.Mescher. Signal three determines tolerance versus full activation of naïve CD8 T cells: uncoupling proliferation and development of effector function. J. Exp. Med. 197:1141-1151, 2003
• Curtsinger,J., F.Popescu and M.F.Mescher. Interferon-a can provide the third signal required for CD8 T cell activation. manuscript in preparation.
• Goldberg,J. and M.F.Mescher. In vivo augmentation of tumor-specific CTL responses by class I/peptide Ag complexes on microspheres (Large Multivalent Immunogen). J. Immunol., in press
• Curtsinger,J.M., F.Popescu and M.F.Mescher. Type I interferon provides a direct link between innate and CD8 T cell adaptive immune responses. manuscript in preparation
• Curtsinger,J.M., D.C.Lins and M.F.Mescher. Signal three determines tolerance versus full activation of naïve CD8 T cells: dissociating proliferation and development of effector function. J. Exp. Med. 197:1141-1151 (2003)
• Curtsinger,J.M., C.M.Johnson and M.F.Mescher. CD8 T cell clonal expansion and development of effector function require prolonged exposure to antigen, costimulation and signal 3 cytokine. J. Immunol. 171: 5165-5171, 2003.
• Oosten,L.E.M., E.Blokland, A.G.S. van Halteren, J.Curtsinger, M.F.Mescher, J.H.F.Falkenburg, T.Mutis and E.Goulmy. Artificial antigen presenting constructs efficiently stimulate minor histocompatibility antigen specific cytotoxic T lymhocytes. Blood 104: 224-226, 2004.
• Valenzuela, J.O., C.Hammerbeck and M.F.Mescher. Bcl-3 upregulation by signal 3 cytokine (IL-12) prolongs survival of Ag-activated CD8 T cells. J. Immunol. cutting Edge, 174:600-604, 2005
• Curtsinger, J.M., J.O. Valenzuela, P. Agarwal, D. Lins and M.F. Mescher. Cutting Edge: Type I interferons provide a third signal to CD8 T cells to stimulate clonal expansion and differentiation. J. Immunol. 174:4465-4469, 2005.
• Filatenkov, A.A., E.L. Jacovetty, U.B. Fischer, J.M. Curtsinger, M.F. Mescher and E. Ingulli. CD4 T cell-depedent conditioning of dendritic cells to produce IL-12 results in CD8-mediated graft rejection and avoidance of tolerance. J. Immunol. 174:6909-6917, 2005.
• Curtsinger, J.M., D.C. Lins, C.M. Johnson and M.F. Mescher. Signal 3 tolerant T cells degranulate in response to antigen but lack granzyme B to mediate cytolysis. J. Immunol. 174:4465-4469, 2005.
• Mescher, M.F., P. Agarwal, K.A. Casey, C.D. Hammerbeck, F.E. Popescu and J.M. Curtsinger.  Activation of naïve CD8 T cells requires three signals.  Immunol. T