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

Publication date: Available online 20 October 2017
Source:Journal of Autoimmunity
Author(s): Elizabeth Gensterblum, Paul Renauer, Patrick Coit, Faith M. Strickland, Nathan C. Kilian, Shaylynn Miller, Mikhail Ognenovski, Jonathan D. Wren, Pei-Suen Tsou, Emily E. Lewis, Kathleen Maksimowicz-McKinnon, W. Joseph McCune, Bruce C. Richardson, Amr H. Sawalha
ObjectiveThe 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.MethodsThe 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.ResultsA 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.ConclusionCD4+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.



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