iNKT cell subsets are associated with distinct clinical manifestations of pulmonary sarcoidosis

Abstract Sarcoidosis is an inflammatory disease of unknown etiology that presents with a wide range of clinical courses, from complete recovery to irreversible lung fibrosis. Invariant Natural Killer T (iNKT) cells are implicated in the progression of many diseases, including sarcoidosis. Given the known phenotypic heterogeneity of this unique T cell subset, we hypothesized that the iNKT cell compartment of individuals with sarcoidosis will have a skewed subset distribution that may track with disease outcome. We used flow cytometry to compare both total iNKT frequencies and distribution of CD4, CD8, CD56, and CD161 subsets in the PBMC of sarcoidosis subjects with a wide range of lung disease severity and healthy controls. We found the lowest iNKT frequencies in subjects with fibrotic lung disease and worst prognosis (Stage IV). This group was also characterized by a higher percentage of CD4/CD8 double-positive (DP) and a lower percentage of CD161+ iNKT cells, a marker profile indicative of recent thymic emigration. In contrast, the percentage of CD56+ iNKT cells correlated directly with a favorable clinical outcome (Stage I), as well as highest total iNKT frequencies among diseased individuals. In summary, we found that distinct iNKT cell subsets tracked with lung disease severity, and may possess different functional properties that directly influence sarcoidosis disease course.