Project 1: Defining the T Cell Mediators of Clinical Response in Chronic GVHD Abstract: Chronic graft versus host disease (cGVHD) represents the major cause of morbidity and late mortality after hematopoietic stem cell transplantation (HCT). While multiple innate and adaptive immune cell populations contribute to its’ pathophysiology, donor T cells orchestrate cGVHD at all stages, either through their direct effects, or through their influence on other cell populations. However, despite detailed information about the mechanisms controlling cGVHD derived from mouse models, and the development of several new clinical therapeutics, the rates of complete response (CR) remain low: most patients demonstrate only a partial response to therapy, and many have therapy-refractory cGVHD. Moreover, there is a critical lack of information about what determines clinical response in individual patients treated for cGVHD. To make breakthroughs in our understanding of the pathogenesis of human cGVHD and to prioritize the next generation of therapeutics, we must (1) Accurately define the immune pathways that are active in patients who ultimately develop cGVHD and (2) Determine the mechanisms of both success and failure of cGVHD treatment regimens at the level of the individual patient. To accomplish these goals, this Project will complete the following Specific Aims. In Aim 1, we will identify Risk Assignment immune profiles for cGVHD at Day +100. In Aim 2, we will determine the evolution of treatment-responsive versus -resistant immune profiles in patients with cGVHD. In Aim 3 we will investigate the impact of gene modification of Tregs based on completed trajectory analyses from responders versus non-responders to low-dose IL-2, in order to create an optimized cellular therapeutic to control cGVHD. By accomplishing these Aims, this Project promises to identify the molecular networks that predict cGVHD, and those associated with response or resistance to cGVHD therapies, thereby paving the way for a new era of successful prevention and treatment strategies for this disease.