Circulating T cells in sarcoidosis have an aberrantly activated phenotype that correlates with disease outcome.

Rationale: Disease course in sarcoidosis is highly variable. Bronchoalveolar lavage fluid and mediastinal lymph nodes show accumulation of activated T cells with a T-helper (Th)17.1 signature, which correlates with non-resolving sarcoidosis. We hypothesize that the peripheral blood (PB) T cell phenotype may correlate with outcome.

Objectives: To compare frequencies, phenotypes and function of circulating T cell populations in sarcoidosis patients with healthy controls (HCs) and correlate these parameters with outcome.

Methods: We used multi-color flow cytometry to quantify activation marker expression on PB T cell subsets in treatment-naïve patients and HCs. The disease course was determined after 2-year follow-up. Cytokine production was measured after T cell stimulation in vitro.

Measurements and main results: We observed significant differences between patients and HCs in several T cell populations, including CD8⁺ and CD4⁺ T cells, Th1/Th17 subsets, CD4⁺ T memory stem cells, regulatory T cells (Tregs) and γδ T cells. Decreased frequencies of CD4⁺ T cells and increased frequencies of Tregs and CD8⁺ γδ T cells correlated with worse outcome. Naïve CD4⁺ T cells displayed an activated phenotype with increased CD25 expression in patients with active chronic disease at 2-year follow-up. A distinctive Treg phenotype with increased expression of CD25, CTLA4, CD69, PD-1 and CD95 correlated with chronic sarcoidosis. Upon stimulation, both naïve and memory T cells displayed a different cytokine profile in sarcoidosis compared to HCs.

Conclusions: Circulating T cell subpopulations of sarcoidosis patients display phenotypic abnormalities that correlate with disease outcome, supporting a critical role of aberrant T cell activation in sarcoidosis pathogenesis.