Highly Activated T-Cell Receptor AV2S3+ CD4+ Lung T-Cell Expansions in Pulmonary Sarcoidosis

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Abstract
Sarcoidosis is a systemic disorder of unknown origin, primarily affecting the lungs. The granulomatous inflammation is driven by the interplay between various molecules and cells, including T cells. Previously, our group reported a close correlation between lung-restricted T-cell receptor (TCR) AV2S3 CD4-positive T-cell expansions and HLA-DR17 in active sarcoidosis. The aim of this study was to characterize phenotypically such AV2S3 lung T cells, to obtain more information about the state of activation of this intriguing T-cell subset. Bronchoalveolar lavage (BAL) was performed on sarcoidosis patients with active disease and on healthy control subjects (HC). The expression of activation and subset markers was evaluated and compared between BAL AV2S3-positive and AV2S3-negative T cells of patients with lung-restricted AV2S3 T-cell expansions, and between BAL and peripheral blood lymphocytes (PBL) of patients and HC. The frequency of cells expressing activation markers CD26, CD28, CD69, and HLA-DR was enhanced in AV2S3-positive versus AV2S3-negative BAL CD4(+) T-cell subsets. In contrast, CD25 (Il-2R) and CD27 were expressed at lower levels by the AV2S3-positive CD4(+) lung T cells. Our data confirm a substantial activation of BAL CD4(+) T cells of patients with sarcoidosis. Furthermore, the AV2S3 CD4-positive lung cells display a pattern of activation markers, suggesting that they are significantly more activated compared with lung CD4(+) T cells expressing other TCR V gene segments as well as compared with BAL CD4(+) T cells of HC. These results support our hypothesis of an ongoing and selective stimulation of AV2S3 T cells by a specific antigen and the participation of this subset in the inflammatory process in the lungs of patients with sarcoidosis.