Date on Master's Thesis/Doctoral Dissertation

8-2010

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Microbiology and Immunology

Committee Chair

Shirwan, Haval

Author's Keywords

Costimulation; Cancer; T regulatory cells; Transplantation; 4-1BBL

Subject

T cells

Abstract

The immune system is of profound importance for host survival due to its ability to clear many acquired diseases. In case of infections and cancer, disease arises due to under-performance of immune system. Whereas in autoimmunity and transplantation, deleterious immunity to normal self-antigens and allogeneic antigens arises due to enhanced immune responses. Regulatory T (Treg) cells play a critical role in immune homeostasis in health and disease. Treg cells are important in the development and maintenance of immune tolerance towards self or transplantation antigens. However, Treg cells also play an obstructive role in cancer-related immunity by suppressing various effector cells. Therefore, development of immunomodulatory approaches that can either promote or inhibit expansion and/or suppressive function of Treg cells in the context of autoimmunity/transplantation and cancer/chronic infections, respectively, is of great importance. Treg cells require three signals, mediated by TCR-MHC-II/peptide (Signal 1), co stimulation (signal 2) and cytokines (signal 3), for development, maintenance and function. Manipulation of any of these signals, therefore, may present an effective approach in modulating Treg cells in the context of various disease settings. The goal of this dissertation is to exploit signal 2 for modulating Treg cells in the setting of cancer and transplantation for immunotherapy. We chose the 4-1BB signaling pathway because of its constitutive expression on Treg cells and its important role in both innate and adaptive immunity. Using a chimeric 4-1BBL (SA-4-1BBL), we herein show that signaling through 4-1BB inhibits antigen and TGF-ß driven conversion of Teff into Treg cells. This effect is primarily mediated by SA-4-IBBL-induced IFN-? production in Teff cells. Importantly, vaccination of mice with established ovalbumin (TAA) expressing EG.7 tumors with SA-4-1BBL results in the blockade of Teff cell conversion into Treg cells within the tumor and spleen. In contrast, SA-4-1BBL in the presence of IL-2 and rapamycin promotes the conversion of naive CD4+ T cells into Treg cells. Provision of three signals (allogeneic TCR stimulation, 4-1BBL mediated co-stimulation, and IL-2 cytokine) in the presence of rapamycin was effective in enhancing the generation/expansion of Treg cells. This is unique to 4-1BB as signaling through CD28 did not increase the generation of Treg cells. Collectively, these novel functions of soluble form of SA-4-1 BBL represent a promising approach to inhibit/promote Treg cell generation/expansion with potential therapeutic applications in cancer immunotherapy and transplantation.

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