Aberrant naive CD4+ T Cell differentiation in systemic juvenile idiopathic arthritis is committed to B cell help

Abstract

ObjectiveSystemic juvenile idiopathic arthritis (sJIA) features characteristics of autoinflammation and autoimmunity, culminating in chronic arthritis. Previous work indicated decreased IFNγ-expression by T helper (Th) cells in sJIA. Here, we hypothesized this to result from aberrant or incomplete Th cell polarization.MethodsCells or sera were obtained from healthy controls (HC, n=26) and sJIA patients (n=61). Isolated naïve Th cells were cultured under Th1, Th17, and T follicular or T peripheral helper (Tf/ph) polarizing conditions and were partly co-cultured with allogenic memory B cells. Surface marker, transcription factor, and/or cytokine expression in peripheral or polarized Th cells or sera as well as B cellular plasma blast generation were studied by flow cytometry, multiplexed bead array assays, ELISA and retrospective RNA profiling analyses.ResultsSJIA naive Th cell differentiation towards Th1 resulted in low IFNγ and Eomesodermin expression. Instead, developing sJIA Th1 cells revealed elevated IL-21 release that negatively correlated with cellular IFNγ and Eomesodermin expression. Both In vitro and ex vivo, IL-21 together with PD-1, ICOS and CXCR5 expression indicated naïve sJIA Th cell differentiation to rather polarize towards a Tf/ph phenotype. Retrospective analysis of whole blood RNA sequencing data demonstrated sJIA-specific overexpression of Bcl-6 as respective master transcription factor. Compared to controls, in vitro generated sJIA Tf/ph cells promoted enhanced B cellular plasma-blast generation.ConclusionIn sJIA pathogenesis skewing of sJIA naïve Th cell differentiation towards a Tf/ph phenotype may represent an echo of autoimmunity, which could shed light on the mechanisms driving the progression towards chronic destructive arthritis.