Immunology
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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

  

This laboratory is interested in analyzing the role of costimulatory molecules in T cell activation in vivo. The approach that we have taken is to focus on the obligatory in vivo role of costimulators using targeted gene disruption. Costimulation is a pivotal event for T cell activation, determining the functional outcome of T cell interaction with antigen presenting cells (activation versus anergy). Learning how to manipulate costimulatory pathways should provide new ways to augment immunity to microbes and tumor antigens, as well as to inhibit the immune response to control transplantation rejection and autoimmunity.

The costimulatory pathway involving the B7-1 and B7-2 costimulatory molecules and their receptors CD28 and CTLA-4 is of major importance. Our studies have revealed striking and unexpected functions 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. As a result of these findings, a second CTLA-4 counter-receptor, B7-2, was cloned. Our studies revealed that B7-2 is the major early activating costimulator in this pathway. Mice lacking both B7-1 and B7-2 exhibit profound immunologic deficits. These 3 B7 deficient strains enable a comparative analysis of the in vivo functions of B7-1 and B7-2, as well as definitive tools for determining when the B7:CD28/CTLA-4 pathway is essential for T cell activation. Our CTLA-4 deficient mouse revealed a critical role for CTLA-4 in turning off activated T cells. This critical negative immunoregulatory function of CTLA-4 provides a previously unsuspected means by which costimulation can regulate responses to self antigens and potentially offers new approaches for manipulating activated T cells. More recently, we have been studying the functions of newly discovered members of the B7-CD28 superfamily (ICOS:B7h and PD-1:PD-L1/PD-L2 pathways). We have recently found that T cells lacking both CD28 and CTLA-4 still exhibit B7 dependent costimulation, suggesting that there are still additional receptors for B7-1 and B7-2.

Current research focuses in three areas. First, we are investigating the role of B7-1 and B7-2 in T cell activation, T cell tolerance, and autoimmune responses. The laboratory is defining mechanisms by which B7 costimulators play a critical role in T cell activation. By examining what factors elicit residual immune responses in mice lacking both B7 costimulators, we are also examining the role of additional costimulatory pathways and the hierarchy of costimulatory pathways through the generation and analysis of mice lacking other costimulatory molecules (including CD48, OX40 ligand, and CD40 ligand). Secondly, we are analyzing the critical negative regulatory role of CTLA-4 in T cell activation and tolerance. A retrovirus-mediated gene transfer approach is being used to carry out a structure-function analysis of CTLA-4 in vivo and to study the biochemical signals downstream of CTLA-4. Finally, we are characterizing the role of the newly identified B7h-ICOS pathway and the role of the PD-1:PD-L1/PD-L2 pathways in regulating T cell activation and tolerance.

Rotation Projects:

  1. Analysis of immune responses of B7 and ICOS deficient strains to model protein antigens, viruses, and parasites, and to self antigens.
  2. Analysis of role of CTLA-4 in T cell tolerance and autoimmunity.
  3. Analysis of the function of the PD-L1 and PD-L2 costimulatory molecules.

 

Papers & Publications:

  1. 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.
  2. Greenwald, RJ, Boussiotis, VA, Lohrsbach, RB, Abbas, AK and Sharpe, AH. CTLA-4 regulates induction of anergy in vivo. Immunity 2001; 14: 145-155.
  3. 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.