Adaptive lymphocyte responses in tolerance and autoimmunity
2022-09
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Adaptive lymphocyte responses in tolerance and autoimmunity
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2022-09
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T cells that encounter self-antigens after exiting the thymus avert autoimmunity through peripheral tolerance. Pathways for this include an unresponsive state known as anergy, clonal deletion, and T regulatory (Treg) cell induction. The transcription factor cues and kinetics that guide distinct peripheral tolerance outcomes remain unclear. In the first part of this dissertation, we report that anergic T cells are epigenetically primed for regulation by the non-classical AP-1 family member BATF. Tolerized BATF-deficient CD4+ T cells were resistant to anergy induction and instead underwent clonal deletion due to pro-apoptotic BIM (Bcl2l11) upregulation. During prolonged antigen exposure, BIM de-repression resulted in fewer PD-1+ conventional T cells as well as loss of peripherally-induced FOXP3+ Treg cells. Simultaneous Batf and Bcl2l11 knockdown meanwhile restored anergic T cell survival and Treg cell maintenance. The data identify the AP-1 nuclear factor BATF as a dominant driver of sustained T cell anergy and illustrate a mechanism for divergent peripheral tolerance fates.
When T cell tolerance breaks down, self-reactive T cell clones may provide aberrant help signals to B cells and trigger an autoimmune response. The specificity of an individual B cell is governed by the antibody molecules that are expressed on the cell surface as the B cell receptor (BCR). Despite processes to select against dangerous BCRs with self-reactivity, rare B cell clones still sometimes manage to escape self-tolerance and mediate autoimmune damage. The precise targets and cellular events that initiate B cell autoimmunity are still not known. Currently, our understanding of autoimmune disease pathogenesis relies on inference from the antibody reactivities that can be readily observed in fully established disease. While these general autoantibody profiles have been useful in diagnosis, they provide limited information about actual pathogenesis. This is because the diversity of self-antigen targets and accompanying autoantibody reactivities greatly expand by the time that an autoimmune disease can be detected. In the second part of this dissertation, we used a novel enrichment strategy to investigate self-reactive B cells in rheumatoid arthritis (RA) – an autoimmune disease with well-defined late-stage autoantibody targeting of citrullinated self-antigens. We identified biased immunoglobulin gene usage in RA subject BCRs. Clustering of related immunoglobulin reads revealed that clonal expansion of rare individual B cell lineages occurs in parallel with divergent sequence mutations. Correspondingly, recombinant monoclonal antibodies (mAbs) generated from such BCR lineages demonstrated citrulline–dependent cross-reactivity extending beyond the citrullinated peptides used for B cell capture. A pair of citrullinated autoantigen–specific mAbs with cross-reactive binding profiles also promoted arthritis in mice. Our findings suggest that broad autoantibody specificities in RA arise from a restricted repertoire of evolving citrulline–multispecific B cell clades with pathogenic potential.
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University of Minnesota Ph.D. dissertation. September 2022. Major: Microbiology, Immunology and Cancer Biology. Advisor: Daniel Mueller. 1 computer file (PDF); viii, 140 pages.
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Titcombe, Philip. (2022). Adaptive lymphocyte responses in tolerance and autoimmunity. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/257048.
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