Beth Israel Deaconess Medical Center
330 Brookline Avenue
Boston, MA 02215
Lab Members: 2 Postdoctoral Fellows, 1 Research Assistant Professor, 1 Graduate Student
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.
1. Patsoukis N, Lafuente EM, Meraner P, Kim Js, Dombkowski D, Li L, Boussiotis VA. RIAM regulates the cytoskeletal distribution and activation of PLC-γ1 in T cells. Science Signaling 2009 Dec 1;2(99): ra79. doi: 10.1126/scisignal.2000409.
2. Lafuente EM, Patsoukis N, Medrano-Fernandez I, Boussiotis VA. RIAM. UCSD-Nature Molecule Pages. 2010. doi:10.1038/mp.a004213.01.
3. Patsoukis N, Brown J, Petkova V, Liu F, Li L, Boussiotis VA. Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation. Science Signaling 2012 Jun 26;5(230): ra46. doi: 10.1126/scisignal.2002796.
4. Wynne JP, Wu J, Su W, Mor A, Patsoukis N, Boussiotis VA, Hubbard SR, Philips MR. Rap1-interacting adapter molecule (RIAM) associates with the plasma membrane via a proximity detector. J Cell Biol. 2012 Oct 15;199(2):317-29. doi: 10.1083/jcb.201201157.
5. Patsoukis N, Li L, Sari S, Petkova V, Boussiotis VA. PD-1 increases PTEN phosphatase activity while decreasing PTEN protein stability by inhibiting CK2. Mol Cell Biol. 2013 Aug;33(16):3091- 8. doi: 10.1128/MCB.00319-13.
Last Update: 1/6/2014