MICaB Graduate Program
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Matthew F. Mescher, Ph.D.
Professor and Kimmelman Chair in Immunology
Department of Laboratory Medicine and Pathology
Harvard University, 1976, Ph.D.
612-626-2368, 612- 626-2403 - office
612-626-2476 - lab
Cytotoxic T lymphocyte activation, signal transduction, immunotherapy
The cytotoxic T lymphocyte (CTL), also known as the killer
cell, plays an important role in immune defense by directly
binding to and killing tumor or virus-infected cells. Dr.
Mescher's laboratory focuses on cell surface receptor interactions
and signaling pathways involved in activation of CTLs. Immunologists
have found that the antigen recognized by the T cell receptor
consists of a peptide bound to major histocompatibility complex
protein on the surface of the target cell. This recognition
initiates a cascade of adhesion and transmembrane signaling
events involving several different receptors on the CTL binding
to cell surface ligands on the target cells. Mescher and his
colleagues are using novel methods for producing artificial
lipid membrane constructs from purified membrane proteins
to sort out these complex signaling events. Molecules known
to be involved in CTL binding and signal transduction, such
as ligands for CD8 proteins and integrins, can be selectively
introduced into these membranes and their specific role in
CTL binding, response, and membrane-cytoskeletal interactions
can be studied. Mescher's work on the molecular basis of T
cell activation has important implications for the development
of novel therapeutic approaches for activating tumor and virus-specific
CTL responses. Artificial membranes made in his laboratory
for in vitro studies of T cell activation augment CTL response
in mice in an antigen-specific manner. The researchers are
now trying to determine how antigen-bound artificial membranes,
particularly membrane-coated latex microspheres, mediate CTL
enhancement and produce therapeutic effects. These findings
would allow for further exploration of the potential for this
approach to immunization and disease therapy.
Selected Recent Publications:
- Gerner, M.Y., L.M. Heltemes-Harris, B.T. Fife, and M.F. Mescher. 2013. Cutting Edge: IL-12 and Type I IFN differentially program CD8 T cells for PD-1 re-expression levels and tumor control. J. Immunol. 191:1011-1015.
- Curtsinger, J.M., P. Agarwal, D.C. Lins and M.F. Mescher. 2012. Autocrine IFN-g promotes naïve CD8 T cell differentiation and syergizes with IFN-a to stimulate strong function. J. Immunol. 189:659-668.
- Gerner, M.Y., K.A. Casey and M.F. Mescher. 2008. Defective MHC-II presentation by DC limits CD4 T cell help for anti-tumor CD8 T cell responses. J. Immunol. 181:155-164.
- Dudek, A.Z., M.F. Mescher, I. Okazaki, V.T. Math, X. Luo, J.M. Curtsinger and J.S. Miller. 2008. Autologous large multivalent immunogen vaccine (LMI) in patients with metastatic melanoma and renal cell carcinoma. Am. J. Clin. Oncol. 31:173-181.
- Mescher, M.F., Curtsinger, J.M., Agarwal, P., Casey, K.A., Gerner, M., Hammerbeck, C.D., Popescu, F. and Xiao, Z.. 2006. Signals required for programming effector and memory development by CD8 T cells. Immunol. Rev. 211:81-92.
- Filatenkov, A.A., Jacovetty, E.L., Fischer, U.B., Curtsinger, J.M., Mescher, M.F. and E. Ingulli. 2005. CD4 T cell-dependent conditioning of dendritic cells to produce IL-12 results in CD8-mediated graft rejection and avoidance of tolerance. J. Immunol. 174: 6909–6917.
- Curtsinger, J.M., J.O. Valenzuela, P. Agarwal, D. Lins and M.F. Mescher .2005. Cutting Edge: Type I interferons provide a third signal to CD8 T cells to stimulate clonal expansion and differentiation. J. Immunol. 174:4465-4469.
- Curtsinger,J.M., D.C.Lins and M.F.Mescher. 2003. Signal three determines tolerance versus full activation of naïve CD8 T cells: dissociating proliferation and development of effector function. J. Exp. Med. 197: 1141-115.
- Curtsinger, J.M., C.S. Schmidt, A. Mondino, D.C. Lins, R.M. Kedl, M.K. Jenkins and M.F. Mescher. 1991. Inflammatory cytokines provide a third signal for act of naive CD4+ and CD8+ T cells. J. Immunol. 162:3256-3262.