Inhibited expression of hematopoietic progenitor kinase 1 associated with loss of jumonji domain containing 3 promoter binding contributes to autoimmunity in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by T cell overactivation and B cell hyper-stimulation. Hematopoietic progenitor kinase 1 (HPK1, also called MAP4K1) negatively regulates T cell-mediated immune responses. However, the role of HPK1 and the mechanisms that regulate HPK1 expression in SLE remain poorly understood. Using chromatin immunoprecipitation (ChIP) microarray data, we identified markedly increased histone H3 lysine 27 trimethylation (H3K27me3) enrichment at the HPK1 promoter of SLE CD4+ T cells relative to controls, and confirmed this observation using ChIP and real-time PCR experiments. We further found that HPK1 mRNA and protein levels were significantly decreased in CD4+ T cells of patients with SLE, and that this decrease was not caused by exposure to standard SLE medications. Down-regulating HPK1 in healthy CD4+ T cells significantly accelerated T cell proliferation and production of IFNγ and IgG. Consistent with these findings, overexpressing HPK1 in SLE CD4+ T cells caused a significant decrease in T cell reactivity. In addition, we observed a striking decrease in jumonji domain containing 3 (JMJD3) binding, but no marked change in enhancer of zeste homolog 2 (EZH2) binding, at the HPK1 promoter region in SLE CD4+ T cells compared to healthy controls. SiRNA knock down of JMJD3 in healthy CD4+ T cells led to decreased JMJD3 binding and increased H3K27me3 enrichment at the HPK1 promoter region, thus inhibiting the expression of HPK1. Concordantly, plasmid-induced overexpression of JMJD3 in SLE CD4+ T cells led to increased JMJD3 binding, decreased H3K27me3 enrichment, and up-regulated HPK1 expression. Our results show for the first time that inhibited HPK1 expression in SLE CD4+ T cells is associated with loss of JMJD3 binding and increased H3K27me3 enrichment at the HPK1 promoter, contributing to T cell overactivation and B cell overstimulation in SLE. These findings suggest that HPK1 may serve as a novel target for effective SLE therapy.

► HPK1 expression is significantly decreased in CD4+ T cells from SLE patients. ► Reduced JMJD3 leads to increased H3K27me3 at the HPK1 promoter in SLE CD4+ T cells. ► Increased H3K27me3 enrichment results in HPK1 down-regulation in SLE CD4+ T cells. ► Decreased HPK1 contributes to abnormal T cell reactivity in SLE.