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The development and function of self-specific CD8 T cells Dhanji, Salim

Abstract

A distinguishing feature of conventional T cells is that they are tolerant to self-peptides that are presented by self-major histocompatibility complex (MHC) molecules even though these cells are positively selected by low affinity interactions between their TCRs and self-peptide/MHC ligands in the thymus. Over the last few years several subsets of unconventional T cells have begun to emerge which often rely on strong interactions between their TCRs and self-antigens for both their development and function. Furthermore, these unconventional T cells often express receptors that are not commonly associated with T cells but rather are associated with cells of the innate immune system. The work in this thesis is focused on the discovery and characterization of a novel subset of CD8 T cells which demonstrate a high affinity for self-antigens and are thus self-specific. These self-specific CD8 T cells can be found in normal mice as well as in self-antigen expressing TCR transgenic mice. Self-specific CD8 T cells are selected by high-affinity interactions either in the thymus or extrathymically and possess a memory-phenotype. As a consequence of this memory-phenotype, which is associated with high expression of CD122 (IL-2Rβ), these cells can proliferate in an antigen-independent manner in response to stimulation with interleukin-2 or -15. Upon activation, the cells express several natural killer cell receptors including NKG2D, CD94, 2B4, and CD16. These NK receptors can act independently or in concert with the self-specific TCR leading to target cell killing and cytokine production. Self-specific CD8 T cells require self-antigen interactions not only for their development but also for the maintenance of their memory-phenotype and cytokine responsiveness. These cells become activated in response to infection or inflammation and this activation results in the innate production of cytokines such as IFNγ which are protective during infection. Thus, self-specific CD8 T cells represent a novel CD8 T cell subset that utilize their TCRs, cytokine receptors as well as NK receptors to provide early protection against infection and the elimination of either stressed or transformed cells.

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