Networked T Cell Death following Macrophage Infection by Mycobacterium tuberculosis.
Citation:
Macdonald SH-F, Woodward E, Coleman MM, Dorris ER, Nadarajan P, et al. (2012) Networked T Cell Death following Macrophage Infection byMycobacterium tuberculosis. PLoS ONE 7(6): e38488Download Item:
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 (<1.5×109 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.
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.
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https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0038488http://hdl.handle.net/2262/89489
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Grant Number
Science Foundation Ireland (SFI)
7/SRC/B1144
Author's Homepage:
http://people.tcd.ie/josephmkDescription:
PUBLISHED
Author: Keane, Joseph
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Journal ArticleURI:
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0038488http://hdl.handle.net/2262/89489
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Series/Report no:
PloS one;7;
6;
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http://dx.doi.org/10.1371/journal.pone.0038488ISSN:
1932-6203Metadata
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