Mycobacterial antigens induce apoptosis in human purified protein derivative‐specific αβ T lymphocytes in a concentration‐dependent manner

Summary The morbidity and lethality of tuberculosis is partially the result of an ineffective delayed‐type hypersensitivity reaction which causes caseating granulomas in the lung and other organs. Recently we showed that during caseation besides macrophages numerous Fas+ FasL+ lymphocytes undergo apoptosis and postulated that this phenomenon may be due to activation‐induced cell death (AICD) as a consequence of T‐lymphocyte reactivation via bacillary antigens. As purified protein derivative of Mycobacterium tuberculosis (Mtb‐PPD) provokes caseation in tuberculosis patients, the question arose as to whether bacillary antigens are responsible for AICD within caseous areas. In the present study Mtb‐PPD‐specific T helper 1 (Th1)‐differentiated T lymphocytes were generated in vitro. Reactivation of these cells with Mtb‐PPD resulted in a concentration‐dependent hyporesponsiveness, which was due to an increase in apoptosis of γδ+, αβ+ CD4+ as well as αβ+ CD8+ T lymphocytes as assessed by the demonstration of the apoptosis‐associated mitochondrial membrane protein 7A6 and DNA fragmentation. Blocking experiments demonstrated that Mtb‐PPD antigens exploited the Fas/FasL system to induce apoptosis in Mtb‐PPD‐specific T lymphocytes. These results may support the hypothesis that in tubercle granulomas with caseation T lymphocytes undergo AICD following reactivation by bacillary antigens, thus contributing to the persistence of tuberculosis.