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Abstract
Understanding the factors that control T cell responses is a major focus of immunology. Despite this the factors that control T cell development, homeostasis and function are still not completely understood. To date the major function of the TNF-family cytokine BAFF is that it is an essential B cell survival and activation factor. The observation that T cells express the BAFF receptors BR3 and TACI suggests a role for BAFF on T cells. This is supported in vitro; exogenous BAFF co-stimulating both human and mouse T cell activation, and in vivo; BAFF Transgenic mice (Tg) have enhanced DTH responses. Conversely blockade of BR3 impairs the development of antigen specific T cell responses. Given the background data on BAFF and T cells, the hypothesis of this thesis was that BAFF would play a potentially powerful pro-inflammatory role in regulating T cell dependent immune responses. To directly assess the affect of BAFF upon T cells the T cell dependent model of allograft rejection was utilised. Contrary to expectations BAFF-Tg mice appeared to have impaired T cell immunity, as indicated by their acceptance of islet allografts. However, further investigation revealed that effector T cell function was intact and the allograft acceptance in BAFF-Tg mice was due to an increased number of CD4+ Foxp3+ regulatory T cells (Tregs). Indeed, depletion of Tregs in BAFF-Tg mice restored normal allo-reactivity demonstrating the expanded Tregs were responsible for maintaining allograft tolerance. The mechanism by which BAFF was expanding Tregs was shown to be independent of the T cell itself and directly related to the presence of B cells. An IL10 B cell regulatory mechanism was then investigated and it was found that although excessive BAFF could expand Tregs in the absence of IL10 they were non functional. In conclusion, the findings presented in this thesis demonstrate that BAFF can play a dichotomous anti-inflammatory role in T cell biology by promoting the expansion of Treg cells that allow for allograft acceptance.