Research Abstract
My research group is investigating mechanisms and signaling pathways involved in regulation of activating and inhibitory T cell responses. Mechanistic understanding of signaling and molecular pathways that regulate T cell responses is of major therapeutic interest in cancer. Specifically, targeted intervention to such pathways provides the means to modulate the immune responses either for augmentation in order to induce anti-tumor immunity or for suppression in order to prevent graft versus host disease, which is the leading cause of non-relapse mortality in patients with hematologic malignancies, who receive allogeneic hematopoietic stem cell transplantation.
Lymphocyte activation requires adhesion to antigen presenting cells. This is a critical event linking innate and adaptive immunity and a mandatory step for the initiation of T cell immune responses. Lymphocyte adhesion is accomplished through the regulation of the principle adhesion molecule on the lymphocyte surface, LFA-1. In order to mediate its adhesive function LFA-1 must be activated via a process referred to as inside-out signaling. Among the few signaling molecules that have been implicated in this process in hematopoietic cells are the small GTPase Rap1 and its downstream effector RIAM, a multidomain protein. RIAM was discovered in our laboratory and defined the MRL class of adaptors. We are studying the dynamic integration of RIAM in signaling assemblies and signal transduction pathways and the mechanistic role of RIAM in the regulation of T cell responses.
Our laboratory was among the first to demonstrate that the induction of T cell anergy in vitro and tolerance in vivo result from active signaling processes. These early observations were verified with the recent developments in the field of immune tolerance and the discovery of the PD-1: PDL1/2 pathway, which has a central and mandatory role in the induction and maintenance of peripheral tolerance. Currently, we are dissecting the mechanisms of PD-1-mediated inhibition of T cell activation at the cellular and signaling level.
Our group is part of hematopoietic stem cell transplantation research team at the Dana-Farber / Harvard Cancer Center (DFCI/HCC). Our ultimate goal is to translate our findings from basic T cell biology into novel approaches for induction of anti-tumor immunity, prevention of GvHD and improvement of immune reconstitution after allogeneic hematopoietic stem cell transplantation.
