A PD‐1highCD4+ T Cell Population With a Cytotoxic Phenotype is Associated With Interstitial Lung Disease in Systemic Sclerosis

Abstract

Objective T cells contribute to tissue injury in systemic sclerosis (SSc), yet the specific T cell subsets expanded in patients with SSc remain incompletely defined. Here we evaluated specific phenotypes and functions of peripheral helper T (Tph) and follicular helper T (Tfh) cells, which have been implicated in autoantibody production, and assessed their associations with clinical features in a well‐characterized cohort of patients with SSc. Methods Mass cytometry of T cells from peripheral blood mononuclear cells of patients with SSc and controls were evaluated using t‐distributed stochastic neighbor embedding visualization, biaxial gating, and marker expression levels. Findings were validated with flow cytometry and in vitro assays. Results The frequencies of PD‐1highCXCR5+ Tfh cells and PD‐1highCXCR5− Tph cells were similar in patients with SSc and controls. t‐distributed stochastic neighbor embedding visualization (tSNE) revealed distinct populations within the PD‐1highCXCR5− cells distinguished by expression of HLA–DR and inducible costimulator (ICOS). Among PD‐1highCXCR5− cells, only the HLA–DR+ICOS− cell population was expanded in patients with SSc. Cytometric and RNA sequencing analyses indicated that these cells expressed cytotoxic rather than B cell helper features. HLA–DR+ICOS− PD‐1highCXCR5− cells were less potent in inducing B cell plasmablast differentiation and antibody production than comparator T helper cell populations. HLA–DR+ICOS−PD‐1highCXCR5− cells were significantly associated with the presence and severity of interstitial lung disease among patients with SSc. Conclusion Among PD‐1highCXCR5− T cells, a subset of HLA–DR+ICOS− cells with cytotoxic features is specifically expanded in patients with SSc and is significantly associated with interstitial lung disease severity. This potential cytotoxicity appearing in the CD4 T cell population can be evaluated as a prognostic disease biomarker in patients with SSc.