MECHANISMS OF CELLULAR IMMUNE RESPONSES

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Our studies emphasize two fundamental areas: 1) characterizing cell surface molecules which facilitate T cell recognition; and 2) analysis of heterogeneity among subsets of human T cells and of the functional capacities of those subsets. Progress has been made in understanding the molecular basis of T cell interactions with endothelium. Two new molecular pathways are being elucidated. A subset of memory T cells bind to the inducible ligand ELAM-1 on endothelial cells; since this pathway does not require prior T cell activation, it may be of primary importance in the initial attachment of memory T cells to inflamed endothelium in vivo. We have defined many characteristics of the molecule CD31 on a subset of T cells which make it a very attractive candidate for regulating T cell adhesion to endothelium. Not only does CD31 mediate adhesion, but it also powerfully induces adhesion by the multiple integrins which are present but relatively nonadhesive on resting T cells. T cell interaction with endothelium via three other molecular pathways: VLA-4/VCAM 1, LFA-l/ICAM-1 and LFA-l/ICAM-2 has also been systematically analyzed. Not only CD3 and CD31, but also the T cell surface molecules CD7 and CD28 can augment the adhesive function of multiple integrins expressed by T cells. Furthermore, adhesion molecules regulate T cell activation, as illustrated by our recent studies with VLA-4/VCAM-1, which confirm and extend ongoing studies of LFA-l/ICAM-1 interactions. Detailed analysis of phenotypic heterogeneity among peripheral blood CD4+ T cells, and more recently CD8+ T cells, identifies marked complexity of regulation of surface phenotype such as: 1) CD4 memory cells can be subdivided into two subsets based on quantitative differences in expression of the CD45RB isoform; 2) Memory cells seem to be much less abundant among CD8 cells than CD4 cells; 3) VLA-4 stands out as an important parameter of differentiation both among CD4 cells and among CD8 cells. In short, our studies highlight and elucidate the relationships between adhesion, activation and differentiation.