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

Document Type

Article

Publication Date

1-1-2018

Publication Title

Journal of autoimmunity

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+CD11ahi 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+CD11ahi 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+CD11ahi T cells with >99% being hypomethylated. RNA sequencing revealed a clear pro-inflammatory transcriptional profile. TCR repertoire analysis suggests less clonotype diversity in KIR+CD11ahi compared to autologous KIR-CD11alow T cells. Similarly, primary KIR+CD11ahi 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+CD11ahi 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+CD11ahi 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.

Medical Subject Headings

Black or African American; CD11a Antigen/metabolism; CD28 Antigens/metabolism; CD4 Antigens/metabolism; Cells; Cultured; DNA Methylation; Disease Progression; Epigenesis; Genetic; Female; Genetic Profile; Humans; Immunophenotyping; Inflammation/immunology; Lupus Erythematosus; Systemic/diagnosis/epidemiology/immunology; Receptors; KIR/metabolism; Risk; Sequence Analysis; RNA; T-Lymphocyte Subsets/immunology; T-Lymphocytes/immunology; United States/epidemiology; Chromatin accessibility; Genetic risk; Lupus; T cells

PubMed ID

29066026

Volume

86

First Page

19

Last Page

28

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