MECHANISMS OF CELLULAR IMMUNE RESPONSES

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Our studies continue to emphasize two fundamental areas: 1) identifying and characterizing the functions of 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. Using multicolor flow cytometry, we have elucidated simplifying principles regarding changes in expression of two classes of molecules during CD4 T cell development which are critical to T cell adhesion: integrins which mediate adhesion and trigger molecules which regulate that adhesion. Among naive T cells there is low homogenous expression of integrins alpha3, alpha4, alpha5, alpha6 and beta1. However, among memory cells there is augmented expression of one or more of these integrins and marked heterogeneity. Among the multiple memory cell subsets distinguished by differential expression of alpha4 and beta1, we have emphasized studies of a subset with high alpha4 but low beta1 expression. Multiple lines of evidence indicate that these represent gut-homing cells, especially our finding that they have uniquely high expression of the integrin alpha4beta7. We have continued our studies of the CD31 molecule with its unique capacity to regulate T cell adhesion. CD31 shows variation in expression of T cells in various secondary lymphoid tissue and nonlymphoid tissue, consistent with a role in regulating T cell migration. Further, it has multiple effects on T cell activation indicating a role in activation of both T cell and monocytes. Finally, we have analyzed early signaling events involved in T-cell activation to determine the contribution by LFA-l/ICAM-1 interaction; these studies demonstrate that it leads to signal transducing events resulting in prolonged phospholipase C (PLC) activation and PIP2 hydrolysis, and a sustained increase in [Ca2+]i level.