CD4+CD28+KIR+CD11 a(hi) T cells correlate with disease activity and are characterized by a pro-inflammatory epigenetic and transcriptional profile in lupus patients

Objective: The goal of this study was to comprehensively characterize CD4+CD28+ T cells over expressing CD11a and KIR genes, and examine the relationship between this T cell subset, genetic risk, and disease activity in lupus. Methods: The size of the CD4+CD28+KIR+CD11a(hi) T cell subset was determined by flow cytometry, and total genetic risk for lupus was calculated in 105 female patients using 43 confirmed genetic susceptibility loci. Primary CD4+CD28+KIR+CD11a(hi) T cells were isolated from lupus patients or were induced from healthy individuals using 5-azacytidine. Genome-wide DNA methylation was analyzed using an array-based approach, and the transcriptome was assessed by RNA sequencing. Transcripts in the CDR3 region were used to assess the TCR repertoire. Chromatin accessibility was determined using ATAC-seq. Results: A total of 31,019 differentially methylated sites were identified in induced KIR+CD11a(hi) T cells with >99% being hypomethylated. RNA sequencing revealed a clear pro-inflammatory transcriptional profile. TCR repertoire analysis suggests less clonotype diversity in KIR+CD11a(hi) compared to autologous KIR-CD11a(low) T cells. Similarly, primary KIR+CD11a(hi) T cells isolated from lupus patients were hypo methylated and characterized by a pro-inflammatory chromatin structure. We show that the genetic risk for lupus was significantly higher in African-American compared to European-American lupus patients. The demethylated D4+CD28+KIR+CD11a(hi) T cell subset size was a better predictor of disease activity in young (age <= 40) European-American patients independent of genetic risk. Conclusion: CD4+CD28+KIR+C011a(hi) T cells are demethylated and characterized by pro-inflammatory epigenetic and transcriptional profiles in lupus. Eliminating these cells or blocking their pro inflammatory characteristics might present a novel therapeutic approach for lupus. (C) 2017 Elsevier Ltd. All rights reserved.