This project is an in vitro study of the hypothesis that certain human gammadelta T cells may bias the CD4+ immune response toward Th1 by selectively lysing Th2 cells in a Fas-dependent manner. It also studies what determinant(s) these gammadelta T cells may recognize. As such this project complements Project 1 which used primarily in vivo murine systems to examine related questions of how MHC class II I-E might promote a Th1 response, and how gammadelta cells might be instrumental in this.
In Aim 1 cytokine profiles of CD4+ PBL and CD4+ synovial lympohocytes will be established using flow cytometry and analysis of supernatants from activated populations. These will then be activated by anti-CD3 in the presence or absence of Vdelta1 cells. After 10 days the cytokine phenotypes of the CD4+ cells will be reassessed to determine whether the Vdelta1 cells promoted a Th1 population. Preliminary studies strongly suggest that human Vdelta1 clones are selectively lytic toward murine Th2 cells. This will be extended to Th1 and Th2 clones and cell lines of human origin in Aim 2 to determine how broadly applicable is the model. In addition, although Th2 clones are highly susceptible to apoptosis by Vdelta1 clones when the targets are about 10 days since their last stimulation, restimulation of the same Th2 clone renders it completely resistant to killing for up to 1 week. This protection appears to be due at least in part to IL4 production. A comparison will be made between the same Th2 clone either 10 days or 3 days since last stimulation. Cells will be examined for differences in surface molecules that might alter susceptibility to killing, including Fas, classical HLA class I and II molecules, as well as non-classical class-I like CD1 family members as well as the recently described MICA/MICB family. Intracellular regulators of apoptosis will also be examined, including bcl-2, bcl-xL, and FAP-1, a Fas-associating phosphatase that is differentially expressed in Th1 vs Th2 cells. Similar to human IEL Vdelta1 cells, our synovial Vdelta1 clones appear to recognize the HLA class I-like molecules, MICA and MICB. This area will be studied in greater detail in Aim 3. MICA and MICB molecules are fairly restricted in their tissue expression and are heat shock inducible. They are expressed by intestinal epithelium, certain lymphoid tunors, but expression on Th1 and Th2 clones has not been examined. It remains to be established whether the synovial Vdelta1 cells actually recognize a determinant expressed by targets such as Th2 cells or Jurkat T cells, or whether the Vdelta1 cells merely express high and prolonged levels of FasL and eliminate Fas high CD4+ cells without actual recognition of them by the Vdelta1 TCR. The first portion of this aim will thus first establish whether there is evidence for activation of Vdelta1 cells by target CD4+ T cells and Jurkat cells using induction of activation markers CD69 and Fas-ligand. If specific Vdelta1 cell activation is observed, it will secondarily consider whether the determinant on Jurkat cells and Th2 cells in MICA or MICB.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
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Special Emphasis Panel (ZAI1)
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University of Vermont & St Agric College
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