Tu150 - The Type 1 Diabetes-associated Risk Variant of BACH2 Alters T Cell Receptor Clonal Diversity in CD4+ Regulatory T Cells and Drives a CD8+ Effector T Cell Phenotype in Pancreatic Lymph Nodes

Richard Musca – University of Florida; Travis Hill – University of Florida; Melanie Shapiro – University of Florida; Maigan Brusko – University of Florida; Todd Brusko – University of Florida

Abstract Text: The transcription factor BACH2 contains a variant conferring risk for Type 1 Diabetes (T1D; rs729298038G>A; OR=1.18; MAF=0.18) and previously linked to reduced expression in naïve human T cells. We sought to examine the impact of BACH2 genotype on tissue phenotypes and T cell receptor (TCR) repertoire from organ donors derived from the Network for Pancreatic Organ donors with Diabetes (nPOD) program. We employed mass cytometry (n=12 control (mean age 16.9; 33% female), n=10 T1D, mean age 19.3, 30% female) and flow cytometry as a validation method (n=18 control, n=6 T1D) to examine immune phenotypes from pancreatic lymph nodes (pLN). We utilized a custom (985,971 loci) Affymetrix array for genotyping samples. Lastly, we assessed TCR (TRB) repertoire clonality by comparing Shannon entropy. We observed that heterozygous (AG) donors possessed more CD8+ T cells co-expressing effector T cell associated chemokine receptors CXCR3 and CXCR5 as compared to homozygous protective (GG) donors (p=0.0165). Moreover, pseudotime analysis of mass cytometry data indicated AG subjects possessed higher mean CD8+ T cell pseudotime, indicative of more terminally differentiated effector T cells (p=0.0362). Accordingly, TRB repertoire analysis revealed increased clonality in sorted pLN CD8+ T cells (p=0.0340) and Tregs (p < 0.0001) from AG donors. These data support a role for the T1D-associated risk allele of BACH2 in controlling CD8+ T cell and Treg immunophenotypes. These findings provide novel insights on how genetic risk variants alter immune regulation in the context of T1D and may offer novel opportunities for therapeutic targeting of this pathway to restore immune tolerance.