FUNCTIONAL SIGNIFICANCE OF T CELL ACTIVATION MARKERS

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DESCRIPTION (Adapted from the Investigator's Abstract): We have come to associate the expression of particular surface determinants with particular stages of T cell differentiation and activation and with certain functions. This is a rational approach that assumes that cells undergoing expansion and acquisition of differentiation effector functions will express different constellations of gene products depending on their position in a maturational continuum. Through correlative experiments and experiments involving cell separation, the field has come to associate markers such as CD45RA and CD62L with immunological naivet, CD45RO and CD29 with memory, and markers such as CD25, CD38 and HLA-DR with activation. Acceptance of this scheme raises the paradox that in AIDS and many other T-cell hyporesponsive conditions the predominant T-cell population in the peripheral circulation expresses markers commonly associated with T-cell activation. The present proposal systematically re-evaluates the functional significance of co-expression of a small group of carefully chosen surface determinants. Guiding this analysis is the underlying notion that the presently accepted categories of mature T cells (naive or unprimed, memory or primed, and activated memory or effector) exclude a population or populations which are present in health but predominate in disease states characterized by lymphopoietic stress. Such a population would have phenotypic attributes in common with activated memory T cells, but would ultimately display differences resulting from their functional (and perhaps maturational) dissimilarities. The objectives of the present proposal, therefore, are 1) to determine the location of major T cell populations in multi-parameter space for freshly isolated normal peripheral blood T cells using 4-color flow cytometry, 2) to measure functions of the major populations chosen to discriminate between known and postulated developmental stages of mature T cells; 3) to quantify populations falling outside of normal multi-parameter space in HIV seropositive subjects and patients early after stem cell transplantation (as a model for lymphopoietic stress); 4) to compare the function of cells falling outside of normal multiparameter space in order to test the competing hypotheses that novel populations represent activated memory T-cells or newly generated pronaive T-cells.