Networked T cell death following macrophage infection by Mycobacterium tuberculosis.

Stephen H-F Macdonald,Wui-Mei Chew,Elliott Woodward,Michelle M Coleman,Parthiban Nadarajan,Anne-Marie Mclaughlin,Joseph Keane,Emma R Dorris,Pere-Joan Cardona

doi:10.1371/journal.pone.0038488

Abstract

BackgroundDepletion 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 FindingsWe found that lymphopenia (<1.5×109 cells/l) was prevalent among culture-positive tuberculosis patients, and lymphocyte counts significantly improved post-therapy. We previously reported that Mtb-infected 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 cell-free 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-α 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 Mtb-secreted 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.ConclusionsMtb-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.

Highlights

Tuberculosis (TB) in an immunosuppressive illness and lymphopenia often occurs in TB patients [1,2]
Mycobacterium tuberculosis (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
Hirsch et al have described an increased susceptibility to apoptosis in T cells taken from tuberculosis patients [15], and research by Sharma et al indicated that infected macrophages can signal T cell apoptosis [16]

Summary

Introduction

Tuberculosis (TB) in an immunosuppressive illness and lymphopenia often occurs in TB patients [1,2]. Significant levels of proapoptotic surface molecules such as Fas ligand are expressed at the periphery of the granuloma, where T cells accumulate [14] This may represent an infection-induced ‘keep out’ signal that prevents T cell penetration into the granuloma centre. Hirsch et al have described an increased susceptibility to apoptosis in T cells taken from tuberculosis patients [15], and research by Sharma et al indicated that infected macrophages can signal T cell apoptosis [16] The mechanism of this T cell death response is unclear, and it is not known if Mtb-infected human alveolar macrophages (AMs) can supply this immunosuppressive death signal. The extent to which Mtb infection of human macrophages affects T cell viability is not well characterised

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Conclusion