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

Abstract

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)-γ expressing and non-expressing subsets of CD161⁺ T cells to determine the relevance of the Th17 pathway in pSS. We quantitated the frequencies of both CD161^- and RORγ-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. While the frequencies of both RORγ⁺ and RORγ^- subsets of CD161⁺ CD4⁺ T cells were increased in peripheral blood from pSS patients, the increase in the RORγ⁺ 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 RORγ^- 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. 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 RORγ⁺ (Th17) CD161⁺ subset might contribute to humoral manifestations of the disease, the RORγ^- (non-Th17) CD161⁺ subset is the one associated with disease activity in pSS patients.