T cell regulation of pathogenic B cell in systemic autoimmunity

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ABSTRACT Systemic lupus erythematosus (SLE, lupus) is characterized by the generation of pathogenic autoantibodies that promote tissue injury, including in the kidney. Pathogenic autoantibodies in lupus undergo affinity maturation and immunoglobulin (Ig) isotype switching in germinal centers (GCs) within secondary lymphoid organs (SLOs), a site of CD4+ T cell-dependent (TD) B cell maturation. Yet, the specific subsets of effector CD4+ T cells that promote autoreactive B development, and the regulation of these cells, are not well defined. T follicular helper (Tfh) cells comprise a subset of CD4+ T helper (Th) cells, phenotypically and functionally distinct from other Th cells, such as the classical the Th1, Th2 and Th17 subsets. I have used model systems to explore Tfh-cell cytokine production and its role in B cell maturation, with the long-term goal to investigate these events in pathogenic autoantibody production in SLE. We show that expression of the transcription factor T-bet is required for Tfh and Th1 cell expansion and IFN-γ production, and viral-specific GC output. Activated STAT4 promotes T-bet expression in Tfh cells, as in Th1 cells, along with IL-21. STAT4 and T-bet expression is driven by IL-12 and IFN-β, which are needed to transcriptionally regulate Tfh cell expansion and co- production of IL-21 and IFN-γ, to enable a proper GC response upon type 1 immune response. Similar to viral infection Tfh and Th1 cells expand and persist in murine and human lupus, with similar patterns of STAT4 and T-bet expression, alongside co-expression of IFN-γ and IL-21. Yet, despite their robust co-production of IFN-γ and IL-21, Tfh and not Th1 cells in murine lupus extinguish T-bet expression over time, with its absence also in human cTfh cells from lupus patients. We hypothesize that the chronic inflammatory milieu of lupus alters the genetic expression of effector Th cells leading to aberrant regulation of pathogenic B cells that contribute to disease. Accordingly, we will explore temporal changes in genetic regulation that functionally impact pathognic Tfh cell and GC B cell developemnt in autoimmune disease compared to an acute type 1 viral infection. We will combine cellular techniques with novel genomic approaches to investigate chromatin architecture influencing functional gene expression, followed by identification of the controlling cis-regulatory elements in a side by side comparison of these T and B cells as disease progresses. This will allow us to explore the temproal interplay of transcriptional regulation, dynamic chromatin architecture and genomic organization in the regulation of pathogenic T and B cells. Using cellular techniques, we will also examine the developmental requirements for the T-bet expressing inflammatory B cell subset. We will determine the cytokines and the T cells that promote the genesis of these autoantibody secreting B cells. Ultimately, this work should help distinguish pathogenic and nonpathogenic effector T cells, aiding new avenues of therapeutic design. `