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

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

doi:10.1016/j.jaut.2017.09.011

CD4+CD28+KIR+CD11a^hi T cells correlate with disease activity and are characterized by a pro-inflammatory epigenetic and transcriptional profile in lupus patients

J Autoimmun. 2018 Jan:86:19-28. doi: 10.1016/j.jaut.2017.09.011. Epub 2017 Oct 20.

Affiliations

¹ Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
² Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; Department of Biochemistry and Molecular Biology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
³ Division of Rheumatology, Henry Ford Health System, Detroit, MI, USA.
⁴ Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA. Electronic address: asawalha@umich.edu.

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.

Keywords: Chromatin accessibility; DNA methylation; Genetic risk; Lupus; T cells.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

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
Lupus Erythematosus, Systemic / epidemiology
Lupus Erythematosus, Systemic / immunology*
Receptors, KIR / metabolism
Risk
Sequence Analysis, RNA
T-Lymphocyte Subsets / immunology*
T-Lymphocytes / immunology*
United States / epidemiology

Substances

CD11a Antigen
CD28 Antigens
CD4 Antigens
Receptors, KIR