Ślebioda, Tomasz Jerzy
Functional analysis of TL1A/DR3 interactions during T cell-mediated immune responses.
University of Southampton, School of Medicine,
Members of the tumour necrosis factor superfamily (TNFSF) are important regulators of inflammation and immunity. TL1A (TNFSF15), ligand for death receptor 3 (DR3), is the most recently discovered member of this superfamily and full understanding of its structure and the role in T cell-mediated immune responses is currently incomplete. DR3 expression is strongly up-regulated on activated T cells, although it also is present on resting CD4+ T cells, while the expression of TL1A is rapidly and transiently upregulated on activated cells of the immune system such as dendritic cells, monocytes and T cells. The research published to date shows that TL1A/DR3 interaction is involved in the pathogenesis of several autoimmune diseases and enhances activation of CD4+ T cells, however very little is known about its role in co-stimulation of CD8+ T cells. Several studies showed that TL1A also acts as a polarizer of the immune response by inducing secretion of IFN-γ, IL-4, IL-10 and/or IL-17A from activated CD4+ T cells, although the results vary depending on the conditions of a given experiment. The research presented in this thesis identifies Toll-like receptors 3 and 4 as the inducers of TL1A expression on dendritic cells. Furthermore, different binding patterns of anti- TL1A monoclonal antibody (raised against the homotrimeric form of TL1A) and DR3.Fc construct to cells transfected with TL1A cDNA and cells naturally expressing TL1A suggest that TL1A may exist as a homo- and heterotrimeric protein. Ecotopic expression of TL1A on J558L tumour cells promotes their elimination in a CD8+ T celldependent manner and renders mice immune to a subsequent challenge with tumour cells. Moreover, TL1A promotes the proliferation and accumulation of antigen-specific CD8+ T cells both in vitro and in vivo as well as their activation and differentiation into cytotoxic T cells in vivo. It also enhances the secondary expansion of endogenous antigen-specific memory CD8+ T cells. The studies presented here also show that TL1A/DR3 interaction enhances the proliferation and activation of CD4+ T cells. CD11c-TL1A transgenic and CD2-TL1A transgenic mice that constitutively express TL1A on dendritic cells and T cells, respectively, show elevated levels of IL-13 and IL- 17A in the secondary lymphoid organs suggesting that in this setting TL1A skews the immune response toward Th2 and Th17 type. Furthermore, CD11c-TL1A transgenic mice develop a striking goblet cell hyperplasia in the ileum. TL1A also enhances regulatory T cell accumulation in vivo. The findings presented in this thesis show that TL1A may have the potential for enhancing vaccines that aim to elicit CD8+ T cell responses and also identify mechanisms by which sustained expression of TL1A could promote pathogenesis in inflammatory bowel disease
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