The STAT4 SLE risk allele rs7574865[T] is associated with increased IL-12-induced IFN-? production in T cells from patients with SLE.

ABSTRACT: OBJECTIVES:Genetic variants in the transcription factor STAT4 are associated with increased susceptibility to systemic lupus erythematosus (SLE) and a more severe disease phenotype. This study aimed to clarify how the SLE-associated intronic STAT4 risk allele rs7574865[T] affects the function of immune cells in SLE. METHODS:Peripheral blood mononuclear cells (PBMCs) were isolated from 52 genotyped patients with SLE. Phosphorylation of STAT4 (pSTAT4) and STAT1 (pSTAT1) in response to interferon (IFN)-?, IFN-? or interleukin (IL)-12, total levels of STAT4, STAT1 and T-bet, and frequency of IFN-?+ cells on IL-12 stimulation were determined by flow cytometry in subsets of immune cells before and after preactivation of cells with phytohaemagglutinin (PHA) and IL-2. Cellular responses and phenotypes were correlated to STAT4 risk allele carriership. Janus kinase inhibitors (JAKi) selective for TYK2 (TYK2i) or JAK2 (JAK2i) were evaluated for inhibition of IL-12 or IFN-?-induced activation of SLE PBMCs. RESULTS:In resting PBMCs, the STAT4 risk allele was neither associated with total levels of STAT4 or STAT1, nor cytokine-induced pSTAT4 or pSTAT1. Following PHA/IL-2 activation, CD8+ T cells from STAT4 risk allele carriers displayed increased levels of STAT4 resulting in increased pSTAT4 in response to IL-12 and IFN-?, and an augmented IL-12-induced IFN-? production in CD8+ and CD4+ T cells. The TYK2i and the JAK2i efficiently blocked IL-12 and IFN-?-induced activation of PBMCs from STAT4 risk patients, respectively. CONCLUSIONS:T cells from patients with SLE carrying the STAT4 risk allele rs7574865[T] display an augmented response to IL-12 and IFN-?. This subset of patients may benefit from JAKi treatment.

SUBMITTER: Hagberg N 

PROVIDER: S-EPMC6029643 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature