Networked T Cell Death Following Macrophage Infection By Mycobacterium Tuberculosis

Abstract

Background: Depletion of T cells following infection by Mycobacterium tuberculosis (Mtb) impairs disease resolution, and interferes with clinical test performance that relies on cell-mediated immunity. A number of mechanisms contribute to this T cell suppression, such as activation-induced death and trafficking of T cells out of the peripheral circulation and into the diseased lungs. The extent to which Mtb infection of human macrophages affects T cell viability however, is not well characterised. Methodology/Principal Findings: We found that lymphopenia (,1.5610 9 cells/l) was prevalent among culture-positive tuberculosis patients, and lymphocyte counts significantly improved post-therapy. We previously reported that Mtbinfected human macrophages resulted in death of infected and uninfected bystander macrophages. In the current study, we sought to examine the influence of infected human alveolar macrophages on T cells. We infected primary human alveolar macrophages (the primary host cell for Mtb) or PMA-differentiated THP-1 cells with Mtb H37Ra, then prepared cellfree supernatants. The supernatants of Mtb-infected macrophages caused dose-dependent, caspase-dependent, T cell apoptosis. This toxic effect of infected macrophage secreted factors did not require TNF-a or Fas. The supernatant cytotoxic signal(s) were heat-labile and greater than 50 kDa in molecular size. Although ESAT-6 was toxic to T cells, other Mtbsecreted factors tested did not influence T cell viability; nor did macrophage-free Mtb bacilli or broth from Mtb cultures. Furthermore, supernatants from Mycobacterium bovis Bacille de Calmette et Guerin (BCG)-infected macrophages also elicited T cell death suggesting that ESAT-6 itself, although cytotoxic, was not the principal mediator of T cell death in our system. Conclusions: Mtb-Infected macrophages secrete heat-labile factors that are toxic to T cells, and may contribute to the immunosuppression seen in tuberculosis as well as interfere with microbial eradication in the granuloma.

Pulmonary tuberculosis and Cryptococcal native knee septic arthritis with osteomyelitis in an immunocompetent patient: Mycobacterial effect on CD4 function and cellular immunity

“…Coleman et al examined the effects of TB infected alveolar macrophages on T cell variability in vitro. Infected macrophages caused a dose dependent, caspase dependent T cell apoptosis [10] . Interestingly, mycobacterial antigens promote the expression of inhibitory cytokines (Transforming growth factor beta (TGF-β), IL 10 and IL 35).…”

“…Yet, the mechanism of TB induced lymphopenia is poorly understood. One possible mechanism includes sequestration of T lymphocytes in highly infected tissues [9] , [10] . An alternative explanation is activation induced apoptosis.…”