MECHANISMS OF CELLULAR IMMUNE RESPONSES

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Our studies continue to be directed at elucidating the mechanisms of T cell recognition, with particular emphasis on antigen independent T cell adhesion as a critical early step in the process of recognition. Major progress has been in understanding the functional role of the ICAM-l molecule which our previous func- tional studies have suggested functions as a ligand for LFA-l. ICAM-l has been purified by immunoaffinity chromatography. Each of two sites on ICAM-l defined by monoclonal antibodies are implicated in its adhesion function. Furthermore, ICAM-l must be an adhesion ligand per se since ICAM-l immobilized on plastic mediates LFA1 dependent adhesion of T, B and myeloid cells. This simplified system of cell binding to ICAM-l allows isolation/analysis in a well defined system of important features of more complex cell interactions including characteristic divalent cation requirements, and a dissociation phase that occurs following the binding phase. Recent studies confirm and extend our previous understanding that human naive and memory cells are distinguished phenotypically by differences in expression not only of adhesion molecules CD2, LFA-3 and LFA-l, but also of several other functional important molecules. We have demonstrated that memory T cells proliferate much more than naive cells when stimulated with CD3 mAb or pairs of CD2 mAb. Such enhanced responsiveness to receptor-mediated triggering is a novel mechanism for T cells which could facilitate memory cell response to specific antigen. Furthermore, stimulation via either CD2 or CD3 results in substantial amounts of gamma interferon production by memory T cells but virtually none by naive cells; thus differentiation from naive to memory cells appears to be accompanied by a stable change in regulation of the gene for gamma interferon. We are in the process of characterizing seven new monoclonal antibodies which are relevant to the foregoing phenotypic and functional studies and appear to identify at least two new molecules.