Networked T cell death following macrophage infection by Mycobacterium tuberculosis.
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.


RESULTS
We found that lymphopenia (<1.5 × 10(9) 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.
Department of Clinical Medicine, Trinity Institute of Molecular Medicine, St James's Hospital, Dublin, Ireland. macdonaldez@gmail.com
Stephen H-F
SH
Macdonald
Elliott
E
Woodward
Michelle M
MM
Coleman
Emma R
ER
Dorris
Parthiban
P
Nadarajan
Wui-Mei
WM
Chew
Anne-Marie
AM
McLaughlin
Joseph
J
Keane
D000942:Antigens, Bacterial / Q000276:immunology; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D018655:Lymphocyte Count; D008231:Lymphopenia / Q000150:complications / Q000453:epidemiology / Q000276:immunology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology / Q000382:microbiology* / Q000473:pathology*; D008970:Molecular Weight; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000276:immunology*; D015995:Prevalence; D015398:Signal Transduction / Q000187:drug effects; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D014376:Tuberculosis / Q000150:complications / Q000453:epidemiology / Q000276:immunology* / Q000382:microbiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019014:fas Receptor / Q000378:metabolism
D000942:Antigens, Bacterial; C491901:FAS protein, human; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D020169:Caspases