Expanded lung T-bet+RORγT+ CD4+ T-cells in sarcoidosis patients with a favourable disease phenotype

Disease phenotypes of pulmonary sarcoidosis are distinguished by clinical rather than immunological criteria. We aimed to characterise patterns of CD4(+) T-cell lineage plasticity underlying the differences in clinical presentation and disease course between the acute form, Lofgren's syndrome, and the heterogeneous, potentially progressive non-Lofgren form. 33 pulmonary sarcoidosis patients and nine controls underwent bronchoscopy with bronchoalveolar lavage. CD4(+) T-cell transcription factor, chemokine receptor and T-cell receptor expression, proliferation and cytokine production were assessed in the lavage fluid and peripheral blood using flow cytometry and multicolour FluoroSpot. CD4(+) T-cells simultaneously expressing the T-helper cell (Th)1 and Th17 transcriptional regulators T-bet and ROR gamma T (T-bet(+)ROR gamma T+) were identified in the lavage, but not blood, of all subjects, and to a significantly higher degree in Lofgren's patients. T-bet(+)ROR gamma T+ cells proliferated actively, produced interferon (IFN)gamma and interleukin (IL)-17A, co-expressed the chemokine receptors CXCR3 and CCR6, and correlated with nonchronic disease. T-cell receptor-restricted V alpha 2.3(+)V beta 22(+) T-cells strongly co-expressed T-bet/ROR gamma T and CXCR3/CCR6. Cytokine production was more heterogeneous in Lofgren's patients, with significantly higher IL-17A, IL-10, IL-22 and IL-2, but lower IFN gamma. Here we demonstrate the presence of lung T-bet(+)ROR gamma T(+)CXCR3(+)CCR6(+) CD4(+) T-cells and Th17-associated cytokines especially in sarcoidosis patients with a favourable prognosis, suggesting a Th1/Th17-permissive environment in the lung with implications for disease resolution.