IMMUNOREGULATORY CIRCUITS IN MAN

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Much progress has been made regarding the functional and phenotypic heterogeneity that exists within the CD4 population based on the expression of different cell surface structures such as CD45 as well as CD29/VLA antigens and the role of these cell surface structures in T cell activation and function. The VLA/CD29 antigens preferentially expressed on the CD45RO+CD45RA- "memory" (helper/inducer) subset and furthermore CD29/VLA integrins can act as signalling receptors in a variety of cell types including T lymphocytes. The details of mechanisms involved in this signalling and subsequent effects upon T cell function are far from clear. Although many surface molecules are reported to be preferentially expressed on CD45RA-CD45RO+ memory T cells and many have focused on the function and activation mechanisms of these cells, little is known about cell surface molecules preferentially expressed on CD45RA+CD45RO-"naive" (suppressor/inducer) cells or about the actual functional programs of this cell subset except for suppressor inducer function. The major goal of this proposal is to determine the structural basis of the regulatory circuits involved in positive and negative immunoregulation by CD4 cell subsets. The specific aims of this proposal are: 1) The structural basis of CD29/VLA-mediated signaling an its role in T cell activation and function. Which VLA-alpha chains are involved in pp105 tyrosine phosphorylation in T cells and the molecular structure of pp105 will be studied. Moreover, biological significance of pp105 nd CD29VLA-mediated signals in subsets of T cells will be determined. 2) The role of CD27 in the functional programs of CD45RA+ T cells. CD45RA+CD27+clones will be established and the role of CD27 in the regulatory function of these clones will be studied. Moreover, the biochemical pathways of CD27 involved in T cell activation and the function of CD27 in T cells utilizing gene transfer methods will be determined. In addition, soluble CD27 molecule will be prepared and the biological effects of soluble CD27 on T cell function and activation as well as the putative ligand for CD27 will be determined. 3) New monoclonal antibody probes to cell surface molecules on CD45RA+ T cells will be developed and their role in the function and activation of these cells will be studied. 4) The molecular and cellular defects in patients with autoimmune diseases. Analysis of the precise T cell phenotypes in patients with autoimmune diseases. Utilizing new monoclonal antibodies (CD27, CD31 and Mabs developed in Aim 3) will be performed. Moreover, the role of VLA/CD29 in activation and function of T cells from patients with autoimmune diseases and the CD27 mediated signals and role of soluble CD27 in T cells from patients with autoimmune diseases will be determined. Our projects would not only provide new data for the molecular mechanisms of T cell activation and T cell immune regulation but will also provide new insights into understanding the pathophysiologic mechanisms of autoimmune diseases such as SLE and Sjogren's syndrome.