CD4+CD28+KIR+CD11ahi T cells correlate with disease activity and are characterized by a pro-inflammatory epigenetic and transcriptional profile in lupus patients. (January 2018)

• Record Type: Journal Article
• Authors: Gensterblum, Elizabeth; Renauer, Paul; Coit, Patrick; Strickland, Faith M.; Kilian, Nathan C.; Miller, Shaylynn; Ognenovski, Mikhail; Wren, Jonathan D.; Tsou, Pei-Suen; Lewis, Emily E.; Maksimowicz-McKinnon, Kathleen; McCune, W. Joseph; Richardson, Bruce C.; Sawalha, Amr H.
• Is Part Of: Journal of autoimmunity. Volume 86(2018)
• Page Start: 19
• Page End: 28
• Publication Date: 2018-01
• Subjects: Lupus -- T cells -- DNA methylation -- Genetic risk -- Chromatin accessibility; Autoimmunity -- Periodicals; Autoimmune diseases -- Periodicals; Autoantibodies -- Periodicals; Autoimmune Diseases -- Periodicals; Auto-immunité -- Périodiques; Maladies auto-immunes -- Périodiques; Electronic journals; 616.978005
• DOI: 10.1016/j.jaut.2017.09.011
• Languages: English
• ISSNs: 0896-8411

Abstract

Abstract: Objective: The goal of this study was to comprehensively characterize CD4+CD28+ T cells overexpressing 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 hypomethylated 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 CD4+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+CD11a 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. Highlights: KIR+CD11a hi T cells can be induced using a DNA methylation inhibitor. Lupus CD4+CD28+KIR+CD11a hi T cells are demethylated and pro-inflammatory. African-American lupus patients have a higher genetic risk score for lupus. KIR+CD11a hi T cells correlate with lupus activity independent of genetic risk.