Mycobacterial growth inhibition is associated with trained innate immunity
Simone A. Joosten, … , Mihai G. Netea, Tom H.M. Ottenhoff
Simone A. Joosten, … , Mihai G. Netea, Tom H.M. Ottenhoff
Published February 20, 2018
Citation Information: J Clin Invest. 2018;128(5):1837-1851. https://doi.org/10.1172/JCI97508.
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Research Article Immunology Infectious disease

Mycobacterial growth inhibition is associated with trained innate immunity

Abstract

The lack of defined correlates of protection hampers development of vaccines against tuberculosis (TB). In vitro mycobacterial outgrowth assays are thought to better capture the complexity of the human host/Mycobacterium tuberculosis (Mtb) interaction. Here, we used a mycobacterial growth inhibition assay (MGIA) based on peripheral blood mononuclear cells to investigate the capacity to control outgrowth of bacille Calmette-Guérin (BCG). Interestingly, strong control of BCG outgrowth was observed almost exclusively in individuals with recent exposure to Mtb, but not in (long-term) latent TB infection, and only modestly in BCG vaccinees. Mechanistically, control of mycobacterial outgrowth strongly correlated with the presence of a CD14dim monocyte population, but also required the presence of T cells. The nonclassical monocytes produced CXCL10, and CXCR3 receptor blockade inhibited the capacity to control BCG outgrowth. Expression of CXCR3 splice variants was altered in recently Mtb-exposed individuals. Cytokines previously associated with trained immunity were detected in MGIA supernatants, and CXCL9, CXCL10, and CXCL11 represent new markers of trained immunity. These data indicate that CXCR3 ligands are associated with trained immunity and are critical factors in controlling mycobacterial outgrowth. In conclusion, control of mycobacterial outgrowth early after exposure to Mtb is the result of trained immunity mediated by a CXCL10-producing nonclassical CD14dim monocyte subset.

Authors

Simone A. Joosten, Krista E. van Meijgaarden, Sandra M. Arend, Corine Prins, Fredrik Oftung, Gro Ellen Korsvold, Sandra V. Kik, Rob J.W. Arts, Reinout van Crevel, Mihai G. Netea, Tom H.M. Ottenhoff

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Figure 3

Capacity to control mycobacterial growth is associated with a CD14dim myeloid population.

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Capacity to control mycobacterial growth is associated with a CD14dim my...
PBMCs were infected with live BCG and rotated for 4 days, and samples were incubated in MGIT tubes in the BACTEC machine. Antibody marker staining for FACS analysis was performed after 16 hours of negative control stimulation. Associations were determined using linear regression modeling (n = 144). (A) The percentage of CD14+ monocytes was positively correlated with mycobacterial growth control. (B) The monocyte/lymphocyte (ML) ratio (% CD14/CD3) correlated with mycobacterial growth control. (C) Representative dot plots of monocyte profiles in individuals with good mycobacterial growth control (more than 1 log reduction of BCG outgrowth compared with the median of the control population), intermediate control (between 1 log reduction and lower limit of the CI of median of control population; see Figure 1G), or no control (above lower limit of the CI of median of control population). There was a strong CD14dim population in the individuals with mycobacterial growth control. (D) Recently exposed individuals had the highest proportion of CD14dim cells; open symbols indicate donors with good control in the MGIA. Controls, n = 37; BCG, n = 16; exposed, n = 50; LTBI, n = 34; TB, n = 19. (E) The percentage of CD14bright monocytes was not correlated with mycobacterial growth control (n = 144). (F) The percentage of CD14dim monocytes was positively correlated with mycobacterial growth control (n = 144).