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

Abstract

SUMMARYThe 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 puri®ed 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-PPDspeci®c 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 cd + , ab + CD4 + as well as ab + 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-speci®c 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.

Serial Serum Leukocyte Apoptosis Levels as Predictors of Outcome in Acute Traumatic Brain Injury

“…APO2.7 is expressed on the mitochondrial membrane during early apoptosis in relation to the release of cytochrome c and represents activation-induced cell death under certain circumstances [34, 35]. In the present study, APO2.7 in all leukocyte subsets was significantly higher in both good and poor outcome TBI groups than in the controls on Day 1.…”

Apoptosis triggered by Rv1818c, a PE family gene from Mycobacterium tuberculosis is regulated by mitochondrial intermediates in T cells

“…Many antigens of M. tuberculosis like PPD interact with T cells during antigen presentation and induce apoptosis in reactive human T cells [6]. T-cell apoptosis is considered to be an important regulatory mechanism of the immune response and is involved in the loss of effector functions during many infectious diseases.…”

“…The onset and subsequent progression of the tuberculosis is often associated with a depression of cellular immunity, as shown by a loss of the tuberculin skin test reaction, a decrease in interleukin-2 (IL-2) secretion, IL-2 receptor (IL-2R) expression and reduction in cell proliferation [2e5]. Thus, in pulmonary tuberculosis, the predominant form of the disease, 17 to 25% of the patients are unresponsive to purified protein derivative (PPD) skin testing and 40 to 60% of the patients have low blastogenic responses to PPD [6,7]. In case of latent infection, M. tuberculosis bacilli can persist within the host in an asymptomatic state and can reactivate years later if the host's immune system wanes such as during HIV infection [8,9].…”

“…However the exact nature of the role played by PE genes in providing survival benefits to macrophages harboring M. tuberculosis from surrounding T cells in granulomas or during pathogenesis associated with infection remains unclear. It has been reported that many antigens including PPD antigen of M. tuberculosis bacilli interact with T cells during antigen presentation and induce apoptosis in reactive human T cells [6,17,18]. Furthermore, M. avium promotes CD8 T cell apoptosis upon exposure to macrophages in mice infection model [19].…”

Mycobacterium bovisBCG Scar Status and HLA Class II Alleles Influence Purified Protein Derivative-Specific T-Cell Receptor Vβ Expression in Pulmonary Tuberculosis Patients from Southern India

“…Patients with chronic hepatitis B show underexpression of TCR V␤ families 14 and 15 and expansion of TCR V␤ family 7 (5). Reactivation of PPD-specific Th1 lymphocytes with PPD resulted in a concentration-dependent hyporesponsiveness due to an increase in apoptosis of ␣␤, ␥␦ CD4 ϩ , and ␣␤ CD8 ϩ cells (30). It is possible that the cells become unresponsive after signaling through their TCR (25).…”