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UBC Theses and Dissertations

Tumor necrosis factor receptor type-2 (p75) functions as a co-stimulator of antigen-driven T cell responses Kim, Edward Yong


Co-stimulation is a fundamental mechanism for self-nonself discrimination in adaptive immunity and encompasses a remarkably dynamic system of receptor-ligand interactions that are spatially and temporally regulated to achieve fine-tuning of T cell responses. In addition to members of the CD28 superfamily, T cell co-stimulation can also be mediated through members of the TNF receptor (TNFR) superfamily. Although TNFα/TNF receptor-2 (TNFR2) interactions were shown to be capable of augmenting T cell proliferation, TNFR2-deficient mice were initially reported to have normal T and B cell compartments, with no apparent defect in T cell function. This thesis re-visited the question applying gene-targeted and TCR transgenic systems to examine the putative co-stimulatory role for TNFα/TNFR2 in controlling T cell responses in vitro and in vivo. My results demonstrate that TNFR2 is an important co-stimulatory molecule for both CD4⁺ and CD8⁺ T cells in promoting IL-2 induction, lowering the activation threshold, and promoting early survival for the dividing population during primary expansion. TNFR2 functions non-redundant of CD28, as TNFR2 is necessary to sustain AKT and NFκB activation, as well as to promote Bcl-XL expression. CD8⁺ TCR transgenic T cells deficient in TNFR2 exhibited dramatic reduction in clonal expansion in vivo upon recombinant Listeria monocytogenes (LM) challenge, which correlated with a survival defect of responding cells and diminished Bcl-2 and survivin expression. The frequency of LM-specific CD4 and CD8 effector T cells was diminished in TNFR2⁻ʹ⁻ mice upon primary challenge with recombinant LM, and led to the generation of a smaller pool of memory T cells. Moreover, TNFR2-deficient mice were more susceptible to a high dose of primary challenge with LM correlating with a marked reduction in the LM-specific in effector T cell pool in vivo. Thus, TNFR2 promotes adaptive immunity as a co-stimulator of T cell responses in both CD4⁺ and CD8⁺ subsets, and represents an interesting therapeutic target for modulating T cell immunity in disease contexts.

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