The vertebrate immune system has the capacity to mount potent, destructive responses in the presence of threatening foreign antigens. A significant element of immune function relates to regulating antigen responses in order to prevent auto-destruction. This regulation, which can be broadly termed """"""""immune tolerance,"""""""" is now known to encompass a variety of active mechanisms. The goal of understanding these mechanisms holds great pathophysiologic and therapeutic significance for the study of allotransplant rejection, autoimmunity, neoplasia and chronic infection. A central event in the initiation of antigen-specific immune responses is the interaction between T cells and antigen presenting cells (APCs). It is now known that one subtype of APCs - the Dendritic Cell (DC) - can be both the most potent activator of T cells as well as a powerful negative regulator, depending on the level and nature and of accessory signals it presents along with antigen. The process by which DCs upregulate accessory ligands for T cell activation is termed """"""""maturation."""""""" Thus, the control of DC maturity is a central process in the regulation of T cell activation and tolerance. We have found that DC maturation is potently inhibited by physiological concentrations of Vitamin D3 and a related analog and that in vivo presentation of a specific alloantigen by vitamin D3-conditioned (immature) DCs results in hyporesponsiveness while unconditioned (mature) DCs mediate potent sensitization to the same antigen. This proposal will test the hypotheses that: (a) DCs conditioned by a Vitamin D3 analog mediate antigen-specific immune tolerance in vivo, (b) Vitamin D3 antagonizes DC maturation by modulating the NF-kB signaling pathway in DCs, and (c) Vitamin D3 contributes to immune homeostasis by maintaining DC immaturity in vivo. These hypotheses will be tested by: (i) the use of murine models of allograft rejection and adoptive transfer of TCR transgenic T cells in which specific T cell/DC interactions can be characterized, (ii) the strategy of blocking individual accessory pathways or administering pharmacological immunosuppressants at the time of DC inoculation, (iii) the in vitro characterization of the functional status of multiple elements of the NF-kB signaling pathway in the presence or absence of Vitamin D3 analog, (iv) the generation of in vivo models of the immune system in which the Vitamin D Receptor has been genetically deleted.
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