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

Mehreen Elahee, Alisa A. Mueller, Runci Wang, Kathryne E. Marks, Takanori Sasaki, Ye Cao, Andrea Fava, Paul F. Dellaripa, Francesco Boin, Deepak A. Rao

Research output: Contribution to journalArticlepeer-review


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+ICOSPD-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.

Original languageEnglish (US)
JournalACR Open Rheumatology
StateAccepted/In press - 2024

ASJC Scopus subject areas

  • Rheumatology


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