DESCRIPTION (provided by applicant): Tumors create a pathological state of tolerance toward their own antigens. Dendritic cells (DCs) may play a key role in this process, because they are critical regulators of the choice between immune activation and systemic tolerance. The applicants have identified a molecular mechanism by which certain DCs can inhibit T cell proliferation via induction of the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO). The current proposal addresses the overall hypothesis that IDO-expressing myeloid DCs are able to block cell-cycle progression in T cells via local depletion of tryptophan, which allows them to inhibit T cell proliferation in vitro, and create tolerance to the antigens they present in vivo. Specifically, Aim 1 will test the hypothesis that signals intrinsic to the process of antigen presentation act synergistically with cytokines derived from regulatory T cells to trigger IDO-mediated inhibition of T cell responses. Within this model, the applicants will test the subsidiary hypothesis that antigen-driven activation in the face of IDO-mediated inhibition forces T cells into a regulatory phenotype. Aim 2 will test the hypothesis that the molecular mechanism by which IDO inhibits cell-cycle progression in T cells is via activation of specific amino-acid sensitive stress-response signaling pathways. Aim 3 will use a defined in vivo model, comprising IDO transfected antigen-presenting cells injected into T Cell Receptor (TCR)-transgenic hosts, to test the hypothesis that IDO expression by antigen-presenting cells allows T cells to recognize antigen and progress into early G1, but causes IDO-dependent cell-cycle arrest in mid-G1, with consequent failure of clonal expansion. Clinically, the failure of the host immune system to respond to tumor-associated antigens represents a major barrier to effective cancer immunotherapy. The applicants hypothesize that IDO-mediated mechanisms may contribute to this pathologic state of acquired tolerance.
|Effective start/end date||7/1/03 → 5/31/19|