Our group investigates mechanisms and signaling pathways involved in regulation of activating and inhibitory T cell responses. Mechanistic understanding of molecular pathways that regulate T cell responses is of therapeutic interest because targeted intervention to such pathways may provide the means to modulate the immune responses either for suppression as in autoimmunity, allergy, asthma, graft rejection and graft versus host disease or for augmentation against pathogens and tumors.
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 as a Rap1 interacting molecule 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 domains in regulation of inside-out integrin activation and 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 an active signaling process. 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) and our ultimate goal is to translate the findings of our basic research into novel approaches for prevention of GvHD and for improvement of immune reconstitution after allogeneic hematopoietic stem cell transplantation.
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