ABSTRACT Candidate: I have focused my clinical and laboratory training on developing a career as a physician/scientist with expertise in hematology/oncology, hematopoietic stem cell transplantation (HSCT) and human immunology. I completed clinical subspecialty training in hematology/oncology in Australia, and then obtained a PhD studying the biology of human dendritic cells (DCs) with Derek Hart with the goal of utilizing DCs to generate virus- and tumor-specific CD8+ T cell responses in patients with B cell malignancies. My postdoctoral training at the Fred Hutchinson Cancer Research Center (FHCRC) with Stanley Riddell has focused on studies of human CD8+ memory T cells, with the goal of understanding intrinsic qualities of different subsets of memory T cells that might predict their role in immune memory and inflammatory disease. In 2008, I began serving as an Attending Physician on the HSCT service, and in 2010 was appointed an Associate in Clinical Research in the Program in Immunology. Career Objectives: My objectives are to understand the mechanisms that regulate human CD161hi CD8+ memory T cells in normal and perturbed homeostasis and to investigate a role for these cells in graft versus host disease (GVHD) and autoimmunity. Research: In work recently published in Immunity, I investigated how human T cell memory is maintained during cytotoxic chemotherapy for acute leukemia, and identified a subset of self-renewing CD8+ T cells that expresses high levels of ABCB1, enabling them to efflux chemotherapy drugs and provide a persistent reservoir of memory T cells during chemotherapy induced lymphocytopenia. They also express genes, including RORC, and CD161 that are associated with production of IL-17, a highly pro-inflammatory cytokine implicated in the pathogenesis of many autoimmune and inflammatory diseases, including GVHD after HSCT. My work has revealed that the type 17-programmed CD161hi subset comprises a remarkably large, and previously unrecognized, proportion (~22%) of the human CD8+ memory T cell pool, and harbors the entire human Tc17 population. Despite their type 17- transcriptional program, only a minority secretes IL-17 or proliferates to ¿CD3 mAb due to regulation of the TCR signaling pathway. TCR signaling pathway regulation can be overcome by provision of costimulation or inflammatory signals, and the nature of those signals dictates the fate of CD161hi cells, resulting in either expansion of cells in the type 17 programmed pool that maintain regulation of TCR signaling or differentiation into IFN-¿ secreting Tc1-like effector cells that are no longer restrained by TCR regulation. These data suggest that the CD161hi CD8+ subset is an extraordinarily large reservoir of type 17-programmed memory cells that can be unleashed in a permissive inflammatory environment, potentially resulting in initiation of an inflammatory cascade. Inflammation induced by conditioning chemo-radiotherapy prior to HSCT could provide the necessary initiating signals that cause loss of TCR regulation or differentiation in CD161hi CD8+ T cells and allow them to contribute to the pathogenesis of GVHD. The specific aims of this proposal are: Aim 1. To characterize mechanisms regulating TCR signal transduction in CD161hi TCM and TEM CD8+ T cells. These studies will localize the sites of downregulation of TCR signaling in CD161hi CD8+ T cells in healthy individuals, thereby indicating potential sites of dysregulation in inflammatory diseases. Aim 2. To characterize the recovery and function of CD161hi CD8+ T cells after myeloablative allogeneic HSCT, and determine if this T cell subset is implicated in GVHD. These studies will determine the kinetics of recovery of CD161hi and CD161lo TCM and TEM CD8+ cells after myeloablative allogeneic HSCT, and if CD161hi CD8+ cell numbers in blood or infiltrated tissue are associated with acute GVHD. I will then establish if TCR signaling pathway regulation is altered in HSCT patients compared to hea |