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Browsing by Subject "Autoimmunity"

Now showing 1 - 6 of 6
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    The function and utility of self-specific CD8 T cells
    (2018-02) Nelson, Christine
    Self-specific CD8 T cells have the potential to provide great benefit, but also to cause great harm. This thesis research seeks to uncover the mechanisms controlling CD8 T cell tolerance to self and tumor antigens. We show that the induction of CD8 T cell tolerance is dependent on inhibitory receptor signaling, but the maintenance of tolerance is not. Thus, only newly primed self-specific CD8 T cell are amenable to immune checkpoint blockade activation. We establish CD8 T cell tolerance as an active state of differentiation that is dependent on suppressed antigen-sensing. We demonstrate that robust stimulation with self-antigen and inflammation induces avidity maturation of the self-specific CD8 T cell repertoire, which serves to renew susceptibility to immune checkpoint and aid in anti-tumor responses. We validate that endogenous self-specific CD8 T cells exist within the immune repertoire and can expanded by similar vaccination methods. Expanded self-specific CD8 T cells generate tissue resident memory in non-lymphoid tissues and secondary lymphoid organs, that are phenotypically distinct from non-self-specific populations. Finally, we show that self-specific CD8 T cells synergize with tumor neo-antigen specific CD8 T cells in the treatment and prevention of cancer. This data provides significant insight into the requirements for the induction of self and anti-tumor T cell responses.
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    Hybrid Peptide-Specific T Cells Incite Islet Inflammation And Autoimmune Diabetes
    (2022-04) Dwyer, Alexander
    Autoimmune diabetes (AD) is a disease characterized by T cell-mediated destruction of the insulin-producing β cells within the islets of Langerhans of the endocrine pancreas. Upon recognition of β cell-specific autoantigen, self-reactive T cells of various specificities expand and migrate to pancreatic islets. Recently, a hybrid peptide derived from the insulin C-chain and chromogranin A (InsC-ChgA) was identified as the cognate antigen for the non-obese diabetic (NOD) mouse-derived diabetogenic BDC-2.5 CD4+ T cell clone, suggesting InsC-ChgA-specific T cells may contribute to disease. Epifluorescent microscopy of pancreatic islets is one approach by which islet T cell inflammation can be assessed in the course of disease altering therapies targeting InsC-ChgA-specific cells, yet most analytical techniques rely upon cumbersome manual estimation of islet infiltration. Importantly, little is known regarding the pathogenicity of InsC-ChgA-specific CD4+ T cells in NOD mice and how selective inhibition of these cells impacts cross-sectional T cell infiltrate area within the pancreatic islets. Here, we first describe a novel approach to achieve rapid, automated, unbiased, and quantifiable data regarding the distribution of islet infiltrating CD4+ and CD8+ T cells in NOD mice. We demonstrate the accurate detection of islet borders using convex hull islet modeling and quantification of T cell infiltrate by writing a macro using the freeware ImageJ. With this method, we assessed CD4+ and CD8+ T cell inflammation within the islets of different age groups of NOD mice progressing towards AD. As proof of technique, we identified significantly more T cell infiltration within convex hull-defined islets of non-diabetic 13-week and 17-week diabetic NOD mice compared to 4-week mice. Second, we focused on the InsC-ChgA-specific CD4+ T cell response in NOD mice and show rapid activation and expansion in neonates. We found that expansion of InsC-ChgA-specific cells requires early interactions with XCR1+ type 1 conventional dendritic cells, and InsC-ChgA-specific cells are clonally restricted with bias towards TRBV15 usage. We also show that adoptive transfer of polyclonal InsC-ChgA-specific cells into NOD.Rag1-/- mice induces AD. Further, spontaneous disease can be suppressed through weekly administration of an InsC-ChgA:I-Ag7-specific monoclonal antibody (mAb). Using the convex hull approach for quantification of T cell infiltration, we identified a substantial decrease in both CD4+ and CD8+ intra-islet infiltration in the nominally pre-diabetic period following InsC-ChgA:I-Ag7 mAb treatment. This thesis describes a novel methodology for the quantifiable assessment of T cell islet infiltration in NOD mice. Additionally, the data here establish the pathogenicity of InsC-ChgA-specific CD4+ T cells, and that immune responses to InsC-ChgA antigen are both necessary and sufficient for AD induction. These results form a framework for future interrogation of other hybrid peptide-specific T cell contributions to AD development in both mice and humans.
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    Immunity and tolerance in the K/BxN model of spontaneous arthritis and endocarditis
    (2013-01) Haasken, Stefanie Sharon
    Immunological tolerance is achieved through multiple mechanisms, including the dominant tolerance exerted by regulatory T cells as well as the induction of anergy in potentially autoreactive lymphocytes. Here, we investigated the role of two molecules of interest, β2 integrins and the class a macrophage scavenger receptor (Msr1), in the pathogenesis of systemic autoimmune disease utilizing the K/BxN TCR transgenic mouse model of spontaneous autoimmune arthritis and endocarditis. Genetic absence of β2 integrins had no effect on the severity of arthritis and unexpectedly increased the extent of cardiovascular pathology. The exaggerated cardiac phenotype of the β2 integrin-deficient K/BxN mice was accompanied by immune hyperactivation and was linked to a defect in regulatory T cells. These findings are consistent with a model in which the development of arthritis in K/BxN mice relies primarily on autoantibodies, whereas endocarditis depends on an additional contribution of effector T cells. K/BxN mice lacking Msr1 had decreased incidence and severity of arthritis. Protection from disease was associated with undetectable levels of antibodies recognizing the key autoantigen in this model, GPI, despite the presence of a population of GPI-specific B cells. Msr1-deficient macrophages displayed impaired uptake of GPI, and Msr1-deficient mice had an elevated concentration of circulating GPI. These data suggest a model in which deficiency of Msr1 can lead to a higher concentration of a soluble autoantigen, resulting in alterations in B cell tolerance and protection from autoimmune disease. Together, these studies contribute to our understanding of the different layers of immunological tolerance responsible for protecting against spurious responses against self.
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    Regulation of autoimmunity and integrin signaling by adaptor proteins ADAP, PRAM-1 and C-CBL
    (2008-12) Zou, Liangxing
    To increase our understanding of adaptor proteins in immune responses, we investigated the roles of adaptor protein ADAP in autoimmune diabetes, and PRAM-1 and c-Cbl in integrin signaling in neutrophils. ADAP deficiency introduced into BDC2.5 transgenic background enhances lymphopenia-stimulated proliferation of autoreactive T cells and autoimmune diabetes, which can be relieved by syngeneic transferred T cells. Further studies suggest that impaired thymic selection, but not defective survival of peripheral T cells, contributes to enhanced lymphopenic stimulation in ADAP-deficient BDC2.5 mice. Therefore, we conclude that ADAP suppresses lymphopenia-dependent autoimmune diabetes through the promotion of thymic output. These data reveal a novel mechanism of autoimmunity regulated by adaptor protein ADAP. When we started to explore the molecular mechanisms regulated by PRAM-1 of integrin signaling in neutrophils, we detected coimmunoprecipitation of c-Cbl and PRAM-1 in NB4 cells. Further, we discovered that c-Cbl positively regulates integrin-dependent oxygen burst but negatively regulates Fc receptor-dependent Ca2+ flux in neutrophils. The underlying molecular mechanisms are currently under investigation. Collectively, data presented in this thesis emphasize the essential roles of adaptor proteins in signal transduction and autoimmunity, and will increase our understanding of adaptor proteins in immune responses.
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    The Role of Anergy in Peripheral Regulatory T cell Generation
    (2016-06) Kalekar, Lokesh
    The role that anergy, an acquired state of T cell functional unresponsiveness, plays in natural peripheral tolerance remains unclear. In this study, we demonstrate that anergy is selectively induced in fetal antigen-specific maternal CD4+ T cells during pregnancy. A naturally occurring subpopulation of anergic polyclonal CD4+ T cells, enriched in self antigen-specific T cell receptors, is also observed in healthy hosts. Neuropilin-1 expression in anergic conventional CD4+ T cells is associated with thymic regulatory T cell (Treg cell)-related gene hypomethylation, and this correlates with their capacity to differentiate into Foxp3+ Treg cells that suppress immunopathology. Thus, our data suggest that not only is anergy induction important in preventing autoimmunity, but it also generates the precursors for peripheral Treg cell differentiation
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    Visualizing CD8+ T cell responses to foreign and self-antigen
    (2017-08) Thompson, Emily
    CD8+ T cells can recognize any infected cell of the body, making them essential in the immune response against intracellular pathogens. A critical function of CD8+ T cells is the directed killing of target cells through cytolysis. This mechanism is dependent on direct cell-cell contact, which makes the migratory capacity of CD8+ T cells paramount to their successful immune response. The small intestine (SI) is the biggest mucosal surface between the host and the environment. The immune system in this compartment must actively eliminate infection while maintaining tolerance to normal flora, self, and food-antigen. Using two-photon laser scanning microscopy, I evaluated foreign- and self-specific CD8+ T cell motility in the SI. I found that foreign-antigen specific CD8+ T cell behavior varied throughout infection, and was independent of the αE integrin. Interestingly, self-specific CD8+ T cells were initially reactive to self-antigen in vivo but this behavior was altered after further tolerance induction. These studies inform our understanding of the requirements for effective CD8+ T cell immunosurveillance in the SI. I also evaluated what characterizes and contributes to a self-specific CD8+ T cell response to protein in the SI. Using a heterologous prime-boost-boost (HPBB) approach, I generated functional self-specific CD8+ T cells. This response matured throughout boosting, showing the potential of self-specific CD8+ T cells. I also used HPBB to evaluate foreign-antigen specific CD8+ T memory development and showed that the time interval between each boost impacts CD8+ T cell memory longevity.