LYMPHOCYTES-T THAT ACCUMULATE IN THE LUNG IN SARCOIDOSIS HAVE EVIDENCE OF RECENT STIMULATION OF THE T-CELL ANTIGEN RECEPTOR

Sarcoidosis, a granulomatous disease of unknown etiology, is characterized at sites of disease such as the lung by the accumulation of large numbers of T-lymphocytes. To differentiate whether the T-cells accumulate in organs nonspecifically (e.g., through chemotaxis or tumorlike proliferation) or more specifically through an antigen-driven ordered immune response, the present study capitalized on the knowledge that specific antigen stimulation of T-cells requires antigen interactions with the T-cell antigen receptor (TCR), resulting in a decrease in the number of surface TCR and a concomitant increase in TCR mRNA levels, i.e., if lung T-cell accumulation in pulmonary sarcoid results from an ordered immune response, lung, but not blood, T-cells should demonstrate evidence of recent triggering of the alpha-beta-receptor, the most abundant type of TCR. The surface density of T-cell surface-alpha-beta-TCR expression was evaluated by flow cytometry with an anti-alpha-beta-antibody and TCR-beta-chain mRNA transcript number quantified by in situ hybridization with S-35-labeled antisense and sense cRNA probes. Control studies utilizing normal blood T-lymphocytes stimulated with the anti-CD3 monoclonal antibody, OKT3, in the presence of autologous monocytes, demonstrated the expected down-regulation of surface-alpha-beta-TCR expression and increased beta-chain mRNA transcript number. When lung and blood T-cells of patients with pulmonary sarcoidosis were compared immediately upon recovery (i.e., without in vitro stimulation), the lung T-cells of 10 of 10 subjects demonstrated a decreased surface density of alpha-beta-TCR compared with their autologous blood T-cells. Furthermore, lung T-cells of eight of nine of these subjects exhibited an increase in beta-chain mRNA transcripts compared with their autologous blood T-lymphocytes. Together, these observations are consistent with the concept that lung, but not blood, T-cells in active pulmonary sarcoidosis have recently been activated through a mechanism that modulates T-cell surface antigen receptor. This process is likely antigen-driven although activation via other ligand-receptor bindings may occur and have not been directly excluded in this study. Overall, these data give support to the hypothesis that the T-cells accumulate in the lung in pulmonary sarcoid in response to persistent antigenic stimulation.