T lymphocyte and NK cell function in pulmonary inflammation in sarcoidosis

Abstract: The focus of this thesis is on the role of T lymphocytes and Natural Killer cells in sarcoidosis, which is an inflammatory interstitial pulmonary disorder of unknown etiology. An accumulation of CD4+ T helper cells in the lungs is a characteristic feature of this disease. Investigation of the cytokine pattern of lung T-cell subsets showed that both CD4+ and CD8+T cells were able to produce high levels of IFNgamma and TNFalpha when compared to peripheral blood T cells, suggesting a Th1 cytokine pattern in BAL T-cells of sarcoidosis patients. In addition, an increased number of cytokine-producing cells in the peripheral blood of patients compared with healthy individuals also demonstrated the systemic nature of the disease. A phenotypic analysis of activation markers on T cells bearing the T cell receptor AV2S3 in BAL fluid revealed that this T cell subset was significantly activated, expressing CD26, CD69 and HLA-DR. This finding is in line with our hypothesis that T cells with the specific T cell receptor AV2S3 have recognized and proliferated in response to a postulated sarcoidosis antigen. Both CD4+ and CD8+ T cells expressed Th1 associated markers i.e. CXCR3, CCR5, IL-12R and IL-18R, suggesting that not only CD4+ T cells play an essential role in contributing to the inflammatory response in sarcoidosis, but also that CD8+ T cells have a major role in this process. A characterization of activation markers on CD4+ T cells in relation to clinical activity revealed increased levels of T regulatory cells, defined as CD4+CD25bright, in patients with active disease. Hypothetically, these cells may be involved in the suppression of cell-mediated immune responses that is typical for sarcoidosis. Finally we demonstrated that Natural Killer (NK) cells in the lungs of patients with pulmonary sarcoidosis displayed a distinct phenotype. The function of these NK cells remains to be determined, although they were able to produce substantial amounts of IFNgamma and TNFalpha, which may be an indication for their participation in the local sarcoid inflammation. Taken together these studies not only emphasize on the importance of accumulated CD4+T cells but also direct the attention to a potentially important role for CD8+ T cells, T regulatory cells and NK cells in the inflammatory process in sarcoidosis.