Anne I. Sperling, Ph.D.

Role of Costimulatory Molecules in T-Cell Responses; T-Cell Regulation of Airway Inflammation

Research Summary

My laboratory is interested in the role of costimulatory and accessory receptors on the regulation of T cell activation and function in Th2-mediated inflammatory responses.

Our work focuses on studying the novel CD28 family member, ICOS. ICOS was originally described as a Th2 specific costimulatory molecule. We have found that ICOS costimualtion regulates Th2 inflammation in a model of asthma. This regulation is at the level of clonal expansion and migration into lymph nodes. The potential of ICOS to regulate effector functions in murine models of allergic airway disease has lead to the speculation that interfering with ICOS-B7RP-1 interactions may provide a novel mode of immunotherapy for allergic asthma as well as autoimmune diseases. New data from our laboratory with human subjects suggest that ICOS expression levels are associated with allergic responses. Together these data suggest that ICOS plays a key role in the regulation of Th2 immune responses.

Another accessory receptor that we are actively studying is the large cell surface mucin, CD43. CD43 is unarguably one of the most abundant proteins on the T cell surface. It has been estimated to cover up to 28% of the surface area on T cells. However, the literature is full of seemingly contradictory findings on the function of this molecule. We have found that the large mucin is actively excluded from T cell/APC interaction sites by linking to the actin cytoskeleton through the Ezrin-Radixin-Moesin (ERM) family of cytoskeletal adaptor proteins. Blocking this movement effects T cell cytokine production and effector function. Further structure-function studies are underway to determine the role of this abundant molecule in the immune response.

Selected Papers

Sperling AI, Sedy JR, Manjunath N, Kupfer A, Ardman B and Burkhardt JK. (1998). Cutting Edge: T cell receptor signaling induces selective exclusion of CD43 from the T-APC contact site. J. Immunol. 161:6459.

Tesciuba AG, Subudhi S, Rother R, Faas SJ, Frantz A, Elliot DE, Weinstock J, Matis LA,  Bluestone JA and Sperling AI. (2001). Inducible costimulator molecule (ICOS) regulates Th2 effector function but not Th2 differentiation in vivo. J. Immunol. 167:1996.

Sperling AI and Bluestone JA. (2001). ICOS costimulation: It's not just for Th2 cels anymore. Nature Immunoogy. 2:573. (News and Views).

Allenspach EJ, Cullinan P, Tang Q, Tong J, Takahashi SM, Morgan R, Burkhardt JK and Sperling AI. (2001). ERM-dependent movement of CD43 defines a novel protein complex distal to the immunological synapse. Immunity. 15:739.

Sperling, A.I. 2001. ICOS costimulation: Is it the key to selective immunotherapy? Clin. Immunol. 100:261.

Cullinan, P., A.I. Sperling,   J.K. Burkhardt. 2002. The distal pole complex: a novel membrane domain distal to the immunological synapse. Immunol Rev. 189:111.

Tong J., E.J. Allenspach, S. Takahashi, P.D. Mody, C. Park, J.K. Burkhardt, A.I. Sperling.  2004.  CD43 regulation of T cell activation is not through steric inhibition of T cell-APC interactions but through an intracellular mechanism.  J.Exp. Med. 199:1277-1283.

Shilling, R.A.,  J.M. Pinto, , D.C. Decker, D.H. Schneider, H.S. Bandukwala, J.R. Schneider, B. Camoretti-Mercado, C. Ober, and A.I. Sperling.  2005. Cutting Edge: Polymorphisms in the ICOS promoter region are associated with allergic sensitization and Th2 cytokine production. J. Immunol. 175(4):2061-5

Tong, J., D.D. Balachandran, R.A. Shilling, R.A. Anders,  H.S. Bandukwala, B.S. Clay, B. Chen, Y. Qin, J.V. Weinstock, P.A. Padrid, J. Solway, K.J. Hamann, and A.I. Sperling.  2006. Fas-positive T cells regulate the resolution of airway inflammation in a murine model of asthma. J. Exp. Med. 203:1173–1184.

Shilling, R.A., H.S. Bandukwala, and A.I. Sperling.  2006. Regulation of T:B cell interactions by the Inducible Costimulator molecule: Does ICOS ‘‘induce’’ disease?  Clinical Immunl. 121(1):13-8.

Bandukwala, H.S., B.S. Clay, J. Tong, P.D. Mody, J.L. Cannon, R.A. Shilling, J.S. Verbeek, J.V. Weinstock, J. Solway and A.I. Sperling.  2007. Signaling through FcγRIII is required for optimal Th2 responses and Th2-mediated airway inflammation. J Exp Med. 204(8):1875-89.

Mody, P.D., J.L. Cannon, H.S. Bandukwala, K.M. Blaine, A. Schilling, K. Swier, and A.I. Sperling. 2007. Signaling through CD43 regulates CD4 T cell trafficking. Blood. 110: 2974-2982.

Clay, B.S., and A.I. Sperling. 2007. T-cell costimulation blockade in immunologic diseases: role of CD28 family members. Expert Review of Clinical Immunology, 3:383-393.