Immunology Graduate Group

Terri H. Finkel
Joseph Lee Hollander Associate Professor of Pediatric Rheumatology

Address:
Center for AIDS Research, 353 BRB II/III or
Division of Rheumatology, 1104 Abramson Research Center
Office: (215) 590-1870
Fax: (215)-590-1258
Email: finkelt@email.chop.edu

Education
Ph.D. (Biochemistry/Biophysics), Stanford University.
M.D., Stanford University
B.S., Stanford University
Master of Arts, Honorary, University of Pennsylvania

Research Interests

Mechanisms of HIV persistence and immune dysregulation, identification of viral and cellular determinants regulating HIV-induced apoptosis, immune suppression and latency

Molecular mechanisms of lymphocyte activation

Research Summary

The Finkel lab focuses on molecular mechanisms of lymphocyte activation in health and disease, with an emphasis on mechanisms of viral persistence and immune dysregulation. Current goals include identification and mechanistic dissection of viral and cellular gene products regulating apoptosis, immune suppression and viral latency. To this end, the Finkel lab has demonstrated that the HIV surface protein, gp120, primes T cells for cell death by apoptosis. These results suggest a mechanism for the massive CD4 T cell depletion in AIDS, particularly in the face of concurrent infection and antigenic challenge with other organisms. Subsequent in vivo studies showed that this apoptosis occurs predominantly in healthy bystander cells and only rarely in infected cells, suggesting that HIV encodes or induces expression of survival genes. Using a variety of molecular techniques including microarray and gene silencing, we have identified known and novel cellular gene products that may regulate T cell apoptosis and latency in HIV infection. Pre-clinical studies are underway to test candidate drugs that may prevent or reverse HIV latency. In other studies defining signaling mechanisms of healthy lymphocytes, we showed that T cells, like some non-immune cells, use the cytoskeleton to transduce activating signals. Current work uses human blood cells and genetically engineered animals to address mechanisms of initiation of T cell activation. A novel artificial membrane system has been developed that closely mimics the cell surface and, in conjunction with real-time digital immunofluorescence microscopy, provides a valuable research tool to study the immune synapse. Finally, we are using animal models, in conjunction with dual photon laser microscopy, to develop novel therapies for autoimmune and infectious disease, including non-myeloablative bone marrow transplantation for lupus, and immune adjuvants for DNA vaccination against agents of bioterror.

Recent Publications

Banda NK, Bernier J, Kurahara DK, Kurrle R, Haigwood N, Sekaly R-P, Finkel TH Crosslinking CD4 by human immunodeficiency virus gp120 primes T cells for activation-induced apoptosis. J Exp Med, 1992

Finkel TH, Banda NK Indirect mechanisms of HIV pathogenesis: how does HIV kill T cells? Curr Opin Immunol, 1994

Finkel TH, Tudor-Williams G, Banda NK, Cotton MC, Curiel T, Monks C, Baba T, Ruprecht R, Kupfer A Apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV- and SIV-infected lymph nodes. Nat Med, 1995

Rozdzial MM, Malissen B, Finkel TH Tyrosine phosphorylated T cell receptor-? chain associates with the actin cytoskeleton upon activation of mature T lymphocytes. Immunity, 1995

Selliah N, Finkel TH Cutting Edge : JAK3 activation and rescue of T cells from HIV gp120-induced unresponsiveness. J Immunol, 1998

Selliah N, Finkel TH Biochemical mechanisms of HIV induced T cell apoptosis. Cell Death Differ, 2001

Selliah N, Finkel TH HIV-1 NL4-3, but not IIIB, inhibits JAK3/STAT5 activation in CD4(+) T cells. Virology, 2001

Kovacs B, Maus MV, Riley JL, Derimanov GS, Koretzky GA, June CH, Finkel TH Human CD8+ T cells do not require the polarization of lipid rafts for activation and proliferation. Proc Natl Acad Sci USA, 2002

Selliah N, Shackelford J, Wang JF, Traynor F, Yin J, Finkel TH T cell signaling and apoptosis in HIV disease. Immunol Res, 2003

Feuerstein N, Shivers D, Chen F, Eisenberg RA, Finkel TH Chronic GVH prevents anergy in bone marrow self-reactive B cells: a selective increase in post-endoplasmic reticulum processing and trafficking to the cell surface of autoreactive IgM receptors. Int Immunol, 2003

Wang J, Marschner S, Finkel TH CXCR4 engagement is required for HIV-1-induced L-selectin shedding. Blood, 2004

Yin J, Chen MF, Finkel TH Differential gene expression during HIV-1 infection analyzed by suppression subtractive hybridization. AIDS, 2004

Feuerstein N, DeSimone DC, Eisenberg RA, Finkel TH Chronic graft-versus-host reaction is associated with a decrease in Ig light chain receptor editing in bone marrow self-reactive B cells. Eur J Immunol, 2004

Maus MV, Kovacs B, Kwok WW, Nepom GT, Schlienger K, Riley JL, Allman D, Finkel TH, June CH Extensive replicative capacity of human central memory T cells. J Immunol, 2004

 

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