Arlene Sharpe
Harvard Medical School
Pathology, NRB-837
77 Avenue Louis Pasteur
Boston, MA 02115
Tel: 617-432-6568
Fax: 617-432-6570
email: asharpe@rics.bwh.harvard.edu
6 Postdoctoral Fellows, 1 Graduate Student
The major interest of the Sharpe laboratory is to study the functions of T cell costimulatory pathways and their immunoregulatory roles in controlling the balance between T cell activation and tolerance. Costimulation is of therapeutic interest because manipulation of T cell costimulatory pathways may provide a means either to enhance immune responses (to promote anti-microbial or tumor immunity) or terminate immune responses (to control autoimmune diseases or achieve tolerance for tissue transplantation). The Sharpe laboratory has used genetic approaches to determine the obligatory functions of T cell costimulatory pathways. Our work has provided novel insights and revealed unexpected functions of costimulatory pathways in the B7:CD28 family of costimulatory pathways. Our studies of B7-1 deficient mice provided the first evidence for the existence of additional functional CD28/CTLA-4 counter-receptors in vivo, and led to the cloning of B7-2. Our studies with CTLA-4 deficient mice revealed a critical role for CTLA-4 in turning off activated T cells, and showed that costimulatory signals not only can stimulate immune responses, but also downregulate immune responses and regulate tolerance in vivo. More recently, we have been characterizing newer pathways within the B7:CD28 family. We have found a critical role for the CD28 homolog ICOS in regulating T cell dependent B cell responses. Our studies in the PD-1:PD-1 ligand pathway have shown that PD-L1 and PD-L2 are ligands for PD-1 and can inhibit naïve and effector T cells. Further work demonstrate a novel role for PD-L1 on parenchymal cells in regulating self-reactive T cells. Additional studies indicate that PD-1 and PD-L1 inhibit T cell function during chronic viral infection and blockade of this pathway can restore function of “exhausted” T cells. These findings have revealed a new therapeutic strategy for chronic viral infection. Recently, we have identified B7-1 and PD-L1 as binding partners and shown that their interaction results in bidirectional inhibition of T cell responses. The identification of this new pathway give increased significance to B7-1 and PD-L1 on T cells, and compels a reassessment of pathways in the B7:C28 family in regulating T cell activation and tolerance.
Current areas of interest in the lab include defining roles of costimulatory and coinhibitory pathways in regulating the balance between pathogenic and protective T cell responses using mouse models of infection and autoimmunity. We are using conditional gene targeting approaches to define the function of coinhibitory receptors on regulatory, effector and memory T cells (as well as other cell types). We also are defining unique and synergistic functions of costimulatory and coinhibitory pathways (e.g., PD-1, CTLA-4, CD160, CD244) during acute and chronic infection and during the induction and maintenance of tolerance. Finally we are beginning to examine how costimulatory and coinhibitory functions in T cells change with with age.
References:
McAdam AJ, Greenwald RJ, Levin MA, Chernova T, Malenkouch N, Ling V, Freeman GJ, Sharpe AH. The Inducible Costimulatory Molecule (ICOS) is Critical for CD40 Mediated Antibody Class Switching. Nature 2001; 409: 102-105.
Greenwald, RJ, Boussiotis, VA, Lohrsbach, RB, Abbas, AK and Sharpe, AH. CTLA-4 regulates induction of anergy in vivo. Immunity 2001; 14: 145-155.
Mandelbrot, DA, Oosterwegel, MA, Shimizu, K, Yamada, A, Freeman, GJ, Mitchell, RN, Sayegh, M, Sharpe, AH. B7-dependent T cell costimulation in mice lacking CD28 and CTLA-4. J. Clin. Investig 2001; 107:881-887.
Immunology webpage updated 8/5/2010