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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Research Article

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 8

Infliximab therapy reduces the antimicrobial activity of PBMCs.

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Infliximab therapy reduces the antimicrobial activity of PBMCs. PBMCs fr...
PBMCs from TST+ patients (n = 4) with active RA or AS were collected before and 2 weeks after the onset of anti-TNF therapy and frozen in liquid nitrogen to allow for simultaneous measurement of antimycobacterial activity. Matched pairs were thawed, and adherent monocytes were infected with M. tuberculosis at MOI 5. Infected monocytes were detached and plated in 24-well plates as described in Methods. Autologous nonadherent cells (1 × 106) were added. (A) The number of viable bacilli was determined by plating the cell lysates at 24 and 96 hours after infection. Shown is the mean ± SEM number of CFUs of all 4 donors tested. (B) Supernatants from the same samples as in A were taken after 24 and 96 hours, and the concentration of IFN-γ was measured by ELISA. Shown is the mean ± SD concentration of IFN-γ of all 4 donors. The IFN-γ concentration in samples containing PBMCs, T cells, and uninfected macrophages was below the 30-pg/ml detection limit.