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 4

CD8+ TEMRA cells lyse M. tuberculosis–infected monocytes and reduce mycobacterial growth.

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CD8+ TEMRA cells lyse M. tuberculosis–infected monocytes and reduce myco...
CD8+ PBMCs were labeled with allophycocyanin-conjugated anti-CD45RA and FITC-conjugated anti-CCR7 and sorted into TEMRA, TEM, and TCM cell subpopulations. (A) Purified T cells were added as effector cells in a 51Cr release assay using autologous M. tuberculosis–infected (MOI 5) or uninfected monocytes as target cells. Supernatants were harvested after 4 hours, and 51Cr release was determined. Shown is mean ± SEM specific lysis of M. tuberculosis–infected monocytes of 4 independent experiments using different TST+ donors. *P < 0.05, infected versus uninfected monocytes. Lysis of uninfected monocytes was generally below 7%. (B) T cell subsets were purified as described above and incubated with infected autologous monocytes (5 × 104 monocytes, 5 × 105 T cells/well). After 36 hours, cells were lysed and plated in 10-fold dilutions on 7H9 agar plates. All samples were set up in duplicate. Shown is mean ± SEM reduction in the number of viable M. tuberculosis cells in monocytes cultured in the presence of T cells compared with monocytes cultured in the absence of T cells. The experiment was performed with 4 each of TST– and TST+ donors. **P < 0.01 versus TST–.