Jonathan Maltzman, M.D., Ph.D.
Assistant Professor of Medicine
University of Pennsylvania
421 Curie Boulevard
754 BRB II/III
Philadelphia, PA 19104
Undergraduate: Undergraduate: Massachussetts Institute of Technology, Cambridge, MA
Medical: University of Pennsylvania School of Medicine, Philadelphia, PA
Residency: University of Chicago, Chicago, IL
Fellowship: Hospital of the University of Pennsylvania, Philadelphia, PA
Board Certification: Internal Medicine and Nephrology
Memory T cells may be generated in response to infection, previous exposure to alloantigens, and lymphopenia. Once generated, memory T cells persist for the lifetime of the host. The Maltzman lab is interested in the intracellular signaling pathways that are involved in the generation, maintenance and activation of these cells.
To address the importance of signals generated by the clontypic T cell receptor (TCR), we have developed a model system in which the critical adaptor protein, SLP-76, is conditionally deleted at various times during an immune response. Lack of SLP-76 abrogates measureable TCR-generated signals in T lymphocytes. This system allows us to generate a normal immune response and then alter the signaling capacity in a defined population of memory T cells. Interestingly, continuous SLP-76 expression is required for the long-term maintenance of CD4+ but not CD8+memory T cells. Studies using a genetic complementation approach are currently underway to determine if the PI3 kinase/AKT, Ras/MAPK and NFkB pathways are crucial for CD4+ memory T cell maintenance.
Long-lived memory T cells are a barrier to successful solid organ transplantation and tolerance induction. In the absence of previous transplantation, it is unclear how an individual would develop alloreactive memory T cells. One possibility is through a process termed heterologous immunity in which memory generated to previous bacterial or viral infection is cross-reactive with foreign tissue. Our laboratory is currently using in vivo models of acute and chronic viral infection to generate immune memory and studying the role of cross-reactive T cells on allograft tolerance and rejection.
Clinical and Other Interests:
Laboratory Web Page: http://www.med.upenn.edu/apps/faculty/index.php/g20000341/p12032
Wiehagen, K.R., E. Corbo, M. Schmidt, H. Shin, E.J. Wherry, and J.S. Maltzman: Loss of tonic TCR signals alters generation but not persistence of CD8+ memory T cells. Blood 116: 5560-5571, 2010.
Bushar, N.D., E. Corbo, M. Schmidt, J.S. Maltzman*# and D.L. Farber*# : Ablation of SLP-76 signaling after T cell priming generates memory CD4 T cells impaired in steady-state and cytokine-driven homeostasis PNAS 107(2): 827-831, January 2010 Notes: * equal contribution # corresponding author.
Wu, G.F., E. Corbo, M. Schmidt, J.E. Smith-Garvin, M.J. Riese, M.S. Jordan, T.M. Laufer, E.J. Brown and J.S. Maltzman: Conditional deletion of SLP-76 in mature T cells abrogates peripheral immune responses Eur J Immunol (in press) 2011 Notes: DOI:10.1002/eji.201040809.
Rahman, A.H., R. Zhang, C.D. Blosser, B. Hou, A.L. DeFranco, J.S. Maltzman, E.J. Wherry, and L.A. Turka: Anti-viral memory CD8 T cell differentiation, maintenance and secondary expansion occur independently of MyD88. Blood 117: 3123-3130, March 2011.
Liu, X., J.L. Karnell, B. Yin, R. Zhang, J. Zhang, P. Li, Y. Choi, J.S. Maltzman, W.S. Pear, C.H. Bassing, and L.A. Turka: Distinct roles for PTEN in prevention of lymphoma and autoimmunity in mice. J Clin Invest 120(7): 2497-2507, July 2010.
Maltzman, J. S., L. Kovoor, J. L. Clements, and G. A. Koretzky: Conditional deletion reveals a cell autonomous requirement of SLP-76 for thymocyte selection. Journal of Experimental Medicine 202(7): 893-900, October 2005.
Maltzman, J.S. and L.A. Turka: Conditional Gene Expression: a new tool for the transplantologist. American Journal of Transplantation 7(4): 733-740, April 2007.
Jordan, M.S.*, J.S. Maltzman*, S. Kliche, J. Shabason, A. Obstfeld, B. Shraven, and G.A. Koretzky: In vivo disruption of T cell development by expression of a dominant-negative polypeptide designed to abolish the SLP-76/Gads interaction. European Journal of Immunology 37(10): 2961-2972, October 2007 Notes: M.S. Jordan and J.S. Maltzman contributed equally to this work.
Maltzman, J.S. and G.A. Koretzky: CD3ε—PeRuSing for positive selection. Nature Immunology 9(5): 457-459, April 2008.
Seet, B.T., D. Berry, J.S. Maltzman, J. Shabason, M. Raina, G.A. Koretzky, C.J. McGlade, and T. Pawson: Efficient T-cell receptor signaling requires a high-affinity interaction between the Gads C-SH3 domain and the SLP-76 RxxK motif. EMBO J 26(3): 678-89, February 2007.