Kohn, L. A. | Search bioRxiv

bioRxiv2024

UTX Epigenetically Imposes a Cytolytic Effector Program in Autoreactive Stem-like CD8+ T cell Progenitors

Type 1 Diabetes Mellitus (T1D) is a chronic disease caused by an unremitting autoimmune attack on pancreatic beta cells. This autoimmune chronicity is mediated by stem-like progenitor CD8+ T cells that continually repopulate the pool of beta cell-specific cytolytic effectors. Factors governing the conversion of progenitors to effectors, however, remain unclear. T1D has been linked to a chromosomal region (Xp13-p11) that contains the epigenetic regulator UTX, which suggests a key role for UTX in T1D pathogenesis. Here, we show that T cell-specific UTX deletion in NOD mice protects against T1D development. In T cells of NOD mice and T1D patients, UTX ablation resulted in the accumulation of CD8+ progenitor cells with concomitant deficiency of effectors, suggesting a key role for UTX in poising progenitors for transition to effectors. Mechanistically, UTXs role in T1D was independent of its inherent histone demethylase activity but instead relied on binding with transcription factors (TCF1 and STAT3) to co-regulate genes important in the maintenance and differentiation of progenitor CD8+ T cells. Together, these findings identify a critical role for UTX in T1D and the UTX:TCF1:STAT3 complex as a therapeutic target for terminating the long-lived autoimmune response.

immunology↗

bioRxiv2022

Reading the canid skeletal story: Coxofemoral joint pathology, and suggested implications for the phylogenetic and natural history of taxa

We evaluated subtle-to-incipient pathology traits in coxofemoral joints from dry bone museum specimens of: Vulpes lagopus; Vulpes; Nyctereutes procyonoides; Urocyon cinereoargenteus; Canis lupus familiaris; and Canis latrans. Multiple intra-articular structures were evaluated on acetabula and proximal femora. Primary observations included multifocal, variable osteophytelike formations; osteophyte-like rimming of articular margins and femoral head (ligamentum teres attachment); and rough or worn bone. Within limitations on valid statistical applications, we observed little difference among the high trait frequencies across taxa, aligning with previous morphological observations. Additionally, for this study, we evaluated the known history of the taxa, from deep time to the present, to consider our data in a phylogenetic context. Potential introgression over the evolution of Canidae, along with early history of the canid genome, likely supported broad and deep conservation of pathophysiological processes associated with observable pathology at the same intra-articular foci, across taxa. We also evaluated the "modern" natural histories of the taxa, noting that coxofemoral joint impacts of their respective life habits did not appear to influence pathology trait outcomes differentially. We conclude that conservation of the physiology underlying subtle and incipient coxofemoral joint pathology that did not segregate among taxa. We hypothesize that the intersecting basic biology of growth-development and insult response, over long geological time, may owe in part to the evidently long histories of hybridization and generally high historical gene flow, with high levels of heterogeneity. These data argue for new research to advance an interdisciplinary, integrated understanding of relationships among canid growth-development, incipient-to-subtle joint pathology, influences of natural histories across related taxa, and implications for genomic interrelationships.

evolutionary biology↗