Gain-of-function (GOF) variants in STAT3 cause a complex disorder characterized by early-onset autoimmunity, lymphoproliferation, recurrent infections, and immune dysregulation. In both primary human and mouse models of STAT3 GOF, CD8+ T cells have been implicated as pathogenic drivers of autoimmunity, though the exact mechanisms remain poorly understood. Here, we found that in patients with STAT3 GOF, CD8+ T cells exist in an activated state. Functional assessment revealed that naive CD8+ T cells have an increased capacity for IFN-γ and TNF-α production, with type I and type II IFN transcriptional signatures. Evaluation of immunoregulatory pathways revealed dysregulation of the purinergic signaling axis in CD8+ T cells: CD39 was increased, whereas downstream purinergic family members, CD73 and the adenosine receptor A2AR, were downregulated, impairing the potential to produce or sense immunosuppressive adenosine. Evaluation of the impact of precision therapy, in the form of JAK inhibition, at a cellular and functional level revealed partial normalization of CD8+ T cell dysregulation in patients, including aberrant cytokine production. Our study suggests that a dysregulated purinergic signaling axis plays a key role in CD8+ T cell dysregulation in STAT3 GOF and may have implications for other rare monogenic immune disorders and common inflammatory disorders.
Jose S. Campos Duran, Montana Knight, Samir U. Sayed et al.· JCI Insight· 0 citations
IL-2-STAT5 signaling is vital for CD4+ T cell function, whereas BACH2 restrains activation. How these transcription factors co-operate at the genome remains unclear. Intracellular C3 supports T cell survival and effector programming, but how it is transcriptionally controlled and whether it matches serum C3 is unknown. We hypothesized that a BACH2-STAT5 module coordinates C3 expression and licenses a distinct C3 proteoform in activated CD4+ T cells.
We profiled wild-type and Bach2—/— CD4+ T cells by RNA-seq and mapped STAT5 and BACH2 binding using ChIP-seq and H3K27ac Hi-ChIP. STAT5 and BACH2 were re-expressed in Stat5—/— T cells, and shared elements at the C3 locus were deleted by CRISPR. IL-2/STAT5 inhibition, C3 overexpression or knockdown, and complement activation assays defined C3 expression and function. AlphaFold2 modeling and domain analyses characterized novel C3 proteoforms.
IL-2/STAT5 target genes were enriched in Bach2—/— CD4+ T cells, with overlapping STAT5 and BACH2 binding at differentially expressed loci. Combined activating or repressive control was confirmed by re-expression in Stat5—/— cells. At the C3 locus, BACH2-STAT5 co-occupancy and IL-2/STAT5 signaling were required for C3 transcription; C3 was lost in Bach2—/— cells, after IL-2/STAT5 blockade, or upon CRISPR deletion of shared elements. Resting CD4+ T cells expressed canonical, signal peptide-containing C3, whereas activation induced a shorter, signal peptide-deficient transcript predicted to encode an intracellular proteoform. Purified short C3 failed to seed classical C3 convertase or support hemolysis, indicating altered function.
We identify a BACH2—STAT5 transcriptional module that is essential for C3 expression in activated CD4+ T cells and redirects C3 output toward a short, intracellular proteoform with noncanonical complement activity. Proteoform-specific, T cell-intrinsic complement suggests new opportunities to target BACH2-STAT5 and C3 in autoimmunity and immunotherapy.
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Immune Response Regulation: Molecular Mechanisms (IRM)
Jorge Trujillo, D. Chauss, Luopin Wang et al.· Journal of Immunology· 0 citations
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