Clinical relevance of RORγ positive and negative subsets of CD161+CD4+ T cells in primary Sjogren's syndrome

Objective. The relevance of the Th17 pathway in primary SS ( pSS) is unclear. Published studies have relied on restimulating circulating CD161 (+) T cells in vitro for quantitation of IL-17-producing cells. While CD161 marks all IL-17(+) T cells, it is also expressed by other Th subsets. The aim of this study was to directly analyse retinoic acid receptor - related orphan nuclear receptor ( ROR) - gamma expressing and non-expressing subsets of CD161(+) T cells to determine the relevance of the Th17 pathway in pSS. Methods. We quantitated the frequencies of both CD161(-) and ROR gamma-expressing T cells by comparative flow cytometry in peripheral blood mononuclear cells from a well-stratified cohort of pSS patients and control subjects. We also analysed the expression of antigen D-related HLA (HLA-DR) and CD161 in labial salivary glands from nine subjects undergoing a diagnostic biopsy. Results. While the frequencies of both ROR gamma (+) and RORg(-) subsets of CD161(+) CD4(+) T cells were increased in peripheral blood from pSS patients, the increase in the ROR gamma + subset positively correlated with humoral manifestations of the disease (anti-SSA/SSB autoantibodies and hypergammaglobulinaemia), but not with disease activity, and vice versa for the ROR gamma(-) subset. An increased frequency of HLA-DR+ CD161(+)CD4(+) T cells was observed in labial salivary gland biopsies from pSS patients, suggesting chronic activation of CD161(+)CD4(+) T cells in the target tissue of the disease. Conclusion. In addition to pointing to CD161 as a marker of a pathogenic subset of CD4 (+) T cells in pSS patients, our data indicate that even though the ROR gamma(+)(Th17) CD161(+) subset might contribute to humoral manifestations of the disease, the RORg(-) (non-Th17) CD161(+) subset is the one associated with disease activity in pSS patients.