The overall aim of the present proposal is the dissection of the CD4+ memory or helper T cell population. Considerable progress has been made in recent years on the functional and phenotypic heterogeneity that exists within the CD4+ population and the role of newly identified cell surface structures in defining the behavior of these cells. Detailed analysis of subsets of human CD4+ lymphocytes indicate that this population is comprised of at least two and most likely several populations which can be differentially triggered by various stimuli to elicit specific functional programs. In this grant proposal I will concentrate mainly on the characterization of the CD4+4B4(CDw29) memory or helper inducer population since this population plays a central role in the immune response by recognizing recall antigens, activating MHC restricted cytotoxic T cells, inducing B cell immunoglobulin synthesis and secreting a variety of biologically potent lymphokines. Considerable evidence suggests that generalized defects in the CD4+ population exists in AIDS and that defects in the memory population may be one of the early manifestations of HIV infection. It is evident that the integrity of the CD4+CDw29+ T cell helper is required not only for specific antibody production, but for the generation of MHC restricted CTL's which can either inhibit HIV viral replication or kill HIV infected autologous target cells. We believe that the ability to carry out many of these functional programs is dictated in part by the cell surface structures which these memory cells express and the cytokines they produce. The projects described in this proposal focus on several antigens expressed on the CD4+ memory cell including 1F7(CDw26) an ectoenzyme with dipeptidyl-peptidase activity), the 180 and 190 KD LCA (CD45) isoforms (protein tyrosine phosphate') and 4B4 (the fibronectin receptor) and other structures. We will characterize the populations of cells expressing these antigens, their patterns of cytokine release and the molecular mechanisms by which these antigens contribute to the functional heterogeneity of the CD4 population. The proposed studies should help identify populations of CD4 cells whose selective function may be related to both differences in lymphokine production and cell surface antigen expression. An understanding of the mechanism by which these cells effect their functional program should provide new insights into the diagnosis and treatment of autoimmune and immunodeficiency diseases.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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AIDS and Related Research Study Section 1 (ARRA)
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Dana-Farber Cancer Institute
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