MECHANISMS OF CELLULAR IMMUNE RESPONSES

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We have questioned longstanding dogmas regarding the physiology and architecture of T-cell dependent area of lymph nodes, and evolved a much richer understanding by a combination of immunohistology, in vivo tracer studies, and cell culture. First, in the T-cell-dependent area T cells migrate in a highly organized labyrinth. The topology of that labyrinth is optimized for efficient cell contact: a) narrow aqueous channels lined b) by stromal cells rich in extracellular matrix suitable for providing traction for cell migration and c) by antigen-presenting interdigitating dendritic cells (IDC) specialized for presenting antigen. Second, there is an effective reticulo-endothelial cell barrier which isolates this compartment from the lymph/sinuses. Third, the movement of soluble tracers from lymph into the T cell dependent areas occurs by transport along an unprecedented conduit system ensheathed by the very stromal cells that form the walls of the labyrinth. Fourth, the stromal cells appear to condition the environment of the lymph node by producing their own soluble factors such as TGFb, and chemokines such as IL-8 and MCP-1. Understanding these features is important to treating diseases where immune responses are deficient (such as cancers) or exaggerated (such as arthritis and diabetes). Moreover, in initial in vitro studies, we find that lymph node stromal cells markedly facilitate T cell infection by HIV virus. We are investigating the morphological and biochemical processes whereby lymphocytes migrate, with particular emphasis on filopodia. We are systematically characterizing human and mouse peripheral blood subsets to understand the ensemble of surfaces molecules expressed by each. In general, better strategies will be required in the biological community to organize the mass of information on human proteins; we are developing an international resource which we designate PROW [Protein Reviews on the Web] to help address this problem.