Anti-TNF immunotherapy reduces CD8+ T cell–mediated antimicrobial activity against Mycobacterium tuberculosis in humans
Heiko Bruns, … , Christian Antoni, Steffen Stenger
Heiko Bruns, … , Christian Antoni, Steffen Stenger
Published April 20, 2009
Citation Information: J Clin Invest. 2009;119(5):1167-1177. https://doi.org/10.1172/JCI38482.
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Anti-TNF immunotherapy reduces CD8+ T cell–mediated antimicrobial activity against Mycobacterium tuberculosis in humans

Abstract

The incidence of tuberculosis is increased during treatment of autoimmune diseases with anti-TNF antibodies. This is a significant clinical complication, but also provides a unique model to study immune mechanisms in human tuberculosis. Given the key role for cell-mediated immunity in host defense against Mycobacterium tuberculosis, we hypothesized that anti-TNF treatment impairs T cell–directed antimicrobial activity. Anti-TNF therapy reduced the expression in lymphocytes of perforin and granulysin, 2 components of the T cell–mediated antimicrobial response to intracellular pathogens. Specifically, M. tuberculosis–reactive CD8+CCR7–CD45RA+ effector memory T cells (TEMRA cells) expressed the highest levels of granulysin, lysed M. tuberculosis, and infected macrophages and mediated an antimicrobial activity against intracellular M. tuberculosis. Furthermore, TEMRA cells expressed cell surface TNF and bound the anti-TNF therapeutic infliximab in vitro, making them susceptible to complement-mediated lysis. Immune therapy with anti-TNF was associated with reduced numbers of CD8+ TEMRA cells and decreased antimicrobial activity against M. tuberculosis, which could be rescued by the addition of CD8+ TEMRA cells. These results suggest that anti-TNF therapy triggers a reduction of CD8+ TEMRA cells with antimicrobial activity against M. tuberculosis, providing insight into the mechanism whereby key effector T cell subsets contribute to host defense against tuberculosis.

Authors

Heiko Bruns, Christoph Meinken, Philipp Schauenberg, Georg Härter, Peter Kern, Robert L. Modlin, Christian Antoni, Steffen Stenger

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Figure 9

CD8+ TEMRA cells rescue antimycobacterial activity of PBMCs from patients during anti-TNF therapy.

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CD8+ TEMRA cells rescue antimycobacterial activity of PBMCs from patient...
PBMCs from 3 consecutive patients with active RA or AS and TST+ were collected before and 2 weeks after beginning of anti-TNF therapy. Adherent cells were infected with virulent M. tuberculosis at MOI 5 for 3 hours, and extracellular bacteria were removed. Of the macrophages, 21% ± 12% were infected (mean ± SD of 3 donors), with each macrophage harboring 1–3 bacilli. Infected monocytes were detached and plated in 24-well plates (5 × 104). Concurrently, CD8+ T cells were purified from the nonadherent fraction and sorted by flow cytometry according to the CD45RA/CCR7 expression profile. CD20+ B cells were purified as a control population. Lymphocyte subsets were added to the infected monocytes (2 × 105) as indicated, and the number of viable bacilli was determined by plating cell lysates after 36 hours of infection. Lysates were plated in 5-fold dilutions and in duplicates. The initial bacterial inoculum was 3.3 ± 0.7 × 104. Shown is the mean ± SEM of 1 experiment with each individual donor. *P < 0.05 versus CFUs cultured in the presence of PBMCs during therapy.