Dendritic cell maturation and T cell immunosurveillance in cutaneous immunity.

摘要

Antigen-specific immunity is dependent on a highly orchestrated collaboration between dendritic cells (DCs) and T cells. In this dissertation, we have investigated two central features of this collaboration. In the first section, we examine the molecular mechanisms that regulate the functional outcome of DC antigen presentation to T cells. In the second section, we examine the homing mechanisms that regulate the development, migration and tissue distribution of antigen-experienced T cells.;When they are mechanically stimulated, murine bone marrow-derived DCs (BMDCs) acquire phenotypic characteristics of maturation yet stimulate antigen-specific T cell non-responsiveness (i.e. tolerance), similar to observations of phenotypically mature yet tolerogenic Langerhans cells in steady state skin-draining lymph nodes (LNs). The molecular details that regulate tolerogenic DC function, and how tolerogenic function is related to maturation status, are not well understood. We elucidate several novel molecular features of the tolerogenic BMDC mechanical response. We demonstrate that DCs respond to mechanical signals using adhesion molecules to activate a unique, constitutively active, beta-catenin-dependent signaling pathway associated with tolerogenic function. Signficantly, we demonstrate a novel mechanism by which an immunosuppressive cytokine may selectively regulate tolerogenic maturation. TGFbeta antagonizes beta-catenin function in BMDCs and thereby selectively suppresses tolerogenic maturation while leaving beta-catenin-independent immunogenic maturation intact.;The chemokine receptor CCR7 plays an important role in DC/T cell collaboration by facilitating their co-localization to LNs. Although CCR7 clearly controls naive T cell entrance into LNs, the role for CCR7 in T cell homing and tissue distribution after encounter with cognate antigen is somewhat controversial. We investigated CCR7 function in the generation and immunosurveillance of antigen-experienced T cells using both long and short-term approaches that require WT and CCR7-deficient populations to directly compete for access to various tissues within an individual animal. We demonstrate that CCR7 is required for efficient tissue-specific imprinting during primary T cell responses, but does not govern T cell homing thereafter. In contrast to previous assumptions, CCR7 does not regulate long-term distribution of antigen-experienced T cells among peripheral and lymphoid tissues. We conclude that CCR7-deficient T cells have undiminished capacity to enter into and exit from skin.