Browsing by Subject "CD8+ T cell"

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    Insights on CD8+ T cell self-tolerance from studies of a polyclonal melanocyte-specific population using a novel mouse model
    (2021-06) Truckenbrod, Emily
    Self-specific CD8+ T cells can escape clonal deletion, but the properties and capabilities of such cells and the mechanisms restraining them require further clarification. Much of the data on self-tolerance originate from mice with genetically-manipulated TCR repertoires, and there is a need for improved models that better recapitulate normal physiology. We established a novel self-tolerance model focused on polyclonal CD8+ T cells specific for tyrosinase-related protein 2 (Trp2), a melanocyte enzyme encoded by the dopachrome tautomerase gene (Dct). We examined mice expressing (wild-type [WT]) or lacking (Dct-/-) this enzyme; Trp2 represents a self-antigen in WT mice and a foreign antigen in Dct-/- mice. Phenotypic and gene expression profiles of pre-immune Trp2/Kb-specific cells were similar; the population size was only slightly reduced in WT relative to Dct-/- mice. Despite comparable initial responses to Trp2 immunization, WT Trp2/Kb-specific cells showed blunted expansion and less readily differentiated into a CD25+ proliferative population. Functional self-tolerance clearly emerged when assessing immunopathology: adoptively transferred WT Trp2/Kb-specific cells mediated vitiligo much less efficiently. Examination of the T cell receptor (TCR) repertoire as characterized by single-cell sequencing revealed clonotypes shared both within and between the WT and Dct-/- Trp2/Kb-specific populations early after activation. Clonal expansions were more frequent among the Dct-/- repertoire, suggesting that higher-performing cells were more likely to be eliminated in WT animals. Our physiologically-relevant model demonstrates that CD8+ T cells can exhibit functional, cell-intrinsic self-tolerance while sharing many features with non-tolerant cells. This model will be useful in further mechanistic investigation of self-tolerance that may ultimately lead to more effective therapeutic manipulation of the immune system.
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    Regulation of cluster of differentiation eight positive (CD8+) T cell homeostatic proliferation.
    (2010-05) Johnson, Lisa Danae Schultz
    The adaptive immune system provides protection against pathogens during a primary infection and generates a reservoir of memory cells that quickly and effectively responds to subsequent encounters with that pathogen for the lifetime of the organism. The goal of modern day vaccination is to generate such memory in the absence of primary infection. Infection or vaccination, however, is not the only method of providing immunological memory. The expansion of T cells in response to lymphopenia, termed homeostatic proliferation, generates memory CD8+ T cells in the absence of cognate antigen and costimulation. Factors such as self-peptide MHC interaction and common-γ chain cytokines are essential for this process. The extent of homeostatic proliferation can be modulated by cytokines that promote and inhibit homeostatic proliferation as well as the sensitivity of the T cell receptor (TCR) to self-peptide MHC. This thesis describes 1) the effect of transforming growth factor beta (TGF-β) on the generation of memory CD8+ T cells and 2) homeostatic proliferation of self- and tumor- specific CD8+ T cells. Collectively, this work provides insights for the design of T cell based vaccines, particularly tumor immunotherapy.
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    Should I stay or should I go: The role of costimulatory signals and S1P receptors in CD8+ T cell trafficking
    (2022-07) Peng, Changwei
    Effective infection control relies on the trafficking of T cells within and between lymphoid and non-lymphoid tissues (NLT) through the circulatory blood and lymph. During immune responses, effector CD8+ T cells can emigrate from secondary lymphoid organs (SLO) to join blood circulation, then migrate into inflamed tissues to conduct functions. After the resolution of infections, some effector T cells survive and maintain their migrating lifestyle in the blood and lymphatic systems, becoming recirculating memory cells. Another population of effector T cells adapt to the NLT environment and are maintained locally without recirculating, becoming resident memory cells (Trm).Recirculating and tissue-resident memory CD8+ T cells provide distinct modes of immune protection, yet the signals dictating the differentiation of these populations are ill-defined. In particular, the interactions within tissues that promote the generation of Trm are unclear. In the first part of this thesis, we show that the inducible costimulatory molecule ICOS is required for CD8+ Trm but not recirculating memory subsets. Furthermore, ICOS engagement during CD8+ T cell recruitment to NLT is critical for efficient Trm establishment: ICOS/ICOS-L interactions are dispensable throughout CD8+ T cell priming and for Trm maintenance, while ICOS-L expression by radioresistant cells is key for optimal Trm generation. Together, this part of the data illustrates that specific local costimulatory cues can promote the production of tissue-resident populations, with potential implications for therapeutic manipulation. The second part of this thesis was focused on understanding the mechanisms that regulate CD8+ T cell egress from SLO into the blood. T cell-intrinsic S1PR1 expression is thought to be indispensable for this process in both naïve and effector populations. However, after different infections, we found diverse dependencies on S1PR1-mediated egress from SLO with activated CD8+ T cells. S1PR1 deficient CD8+ T cells can efficiently traffic into the blood after LCMV but not influenza virus infection. The mechanisms that activated CD8+ T cells utilized to emigrate SLO are still in exploration. Our findings contrast with a widely accepted model that envisages S1PR1 expression as a prerequisite for CD8+ T cell trafficking in the blood.