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 3

The majority of CD8+ and granulysin+ or perforin+ T cells are effector cells.

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The majority of CD8+ and granulysin+ or perforin+ T cells are effector c...
PBMCs from healthy donors were stained with PerCP- or allophycocyanin-conjugated anti-CD8 and anti-granulysin (detected with donkey anti-rabbit biotin and streptavidin) or PE-conjugated perforin. Additional labeling was performed using allophycocyanin-conjugated anti-CD45RA and FITC-conjugated anti-CCR7 to detect TEM cells, PE-conjugated anti-CD161 and FITC-conjugated anti-Vα24 to detect NKT cells, and PE-conjugated CD56 and FITC-conjugated anti-CD16 to detect NK cells. Samples with appropriate isotypes were included in all experiments. (A) CD8+granulysin+ cells were gated, and the expression of additional markers within this gate was determined. Numbers denote the percentage of positive effector cells, NKT cells, or NK cells within the population of CD8+granulysin+ cells. For each sample, 1 × 106 cells were acquired. Shown is a typical result of 8 donors. (B) CD8+perforin+ cells were gated, and the expression of additional markers within this gate was determined. Numbers denote the percentage of positive effector cells, NKT cells, or NK cells within the population of CD8+perforin+ cells. For each sample, 1 × 106 cells were acquired. Shown is a typical result of 4 donors.