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 set of corridors. The topology of those corridors 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. We are investigating the morphological and biochemical processes whereby lymphocytes adhere and migrate. Regulated changes in T lymphocyte cytoskeleton are essential to T cell migration and recognition, both in LN and elsewhere. We are investigating morphological and biochemical changes involved in these processes. We find that changes in intracellular calcium regulate both cytoskeleton and morphology at multiple steps in these processes, including: a) induction of microvilli, which we believe are critical in the process of surveillance in the LN corridors; b) signaling effective interaction by the T cell receptor; and c) inducing acute actin polymerization. Furthermore, we are investigating the assembly of a highly specific complex molecular complex at the site of adhesion/interaction of T cells with CD3-coated beads, as a simplified model in which to understand in detail what happens when T cells encounter antigen-positive cells.