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Early IL-10 promotes vasculature-associated CD4+ T cells unable to control Mycobacterium tuberculosis infection
Catarina M. Ferreira, … , António G. Castro, Egídio Torrado
Catarina M. Ferreira, … , António G. Castro, Egídio Torrado
Published September 23, 2021
Citation Information: JCI Insight. 2021;6(21):e150060. https://doi.org/10.1172/jci.insight.150060.
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Research Article Immunology Infectious disease

Early IL-10 promotes vasculature-associated CD4+ T cells unable to control Mycobacterium tuberculosis infection

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Abstract

Cytokine-producing CD4+ T cells play a crucial role in the control of Mycobacterium tuberculosis infection; however, there is a delayed appearance of effector T cells in the lungs following aerosol infection. The immunomodulatory cytokine IL-10 antagonizes control of M. tuberculosis infection through mechanisms associated with reduced CD4+ T cell responses. Here, we show that IL-10 overexpression only before the onset of the T cell response impaired control of M. tuberculosis growth; during chronic infection, IL-10 overexpression reduced the CD4+ T cell response without affecting the outcome of infection. IL-10 overexpression early during infection did not, we found, significantly impair the kinetics of CD4+ T cell priming and effector differentiation. However, CD4+ T cells primed and differentiated in an IL-10–enriched environment displayed reduced expression of CXCR3 and, because they did not migrate into the lung parenchyma, their ability to control infection was limited. Importantly, these CD4+ T cells maintained their vasculature phenotype and were unable to control infection, even after adoptive transfer into low IL-10 settings. Together our data support a model wherein, during M. tuberculosis infection, IL-10 acts intrinsically on T cells, impairing their parenchymal migratory capacity and ability to engage with infected phagocytic cells, thereby impeding control of infection.

Authors

Catarina M. Ferreira, Ana Margarida Barbosa, Palmira Barreira-Silva, Ricardo Silvestre, Cristina Cunha, Agostinho Carvalho, Fernando Rodrigues, Margarida Correia-Neves, António G. Castro, Egídio Torrado

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Figure 1

Early, but not late, IL-10 overexpression affects the outcome of aerogenic M. tuberculosis infection.

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Early, but not late, IL-10 overexpression affects the outcome of aerogen...
B6 and pMT-10 mice were infected with M. tuberculosis H37Rv via aerosol route and IL-10 overexpression induced after day 5 after infection (A–F). (A) Lung bacterial burdens and (B) survival of B6 and pMT-10 mice following M. tuberculosis infection. (C) Representative hematoxylin and eosin–stained lung sections and percentage of infiltrated area in the lungs at day 40 after infection. Individual data points represent individual animals. Lung bacterial burdens and survival and histology data are representative of 3 independent experiments with 4–5 mice per group. (D) IL-10 concentration in lung supernatants at day 30 after infection, determined by ELISA. Data represent a composite of 5 independent experiments with 4–5 mice per group. **P < 0.01; ***P < 0.001; ***P < 0.0001 using Student’s t test. (E) Lung bacterial burden and (F) percentage of lung infiltrated area at day 40 after infection in B6 and pMT-10 mice that were injected weekly with an anti–IL-10R or control Ab starting 1 day before infection. (E and F) Data are representative of at least 3 independent experiments with 5 mice per group. **P < 0.01 by 1-way ANOVA followed by Tukey’s test. B6 and pMT-10 mice were infected with M. tuberculosis H37Rv via aerosol route and IL-10 overexpression induced at day 30 after infection (G and H). (G) Lung bacterial burden of B6 and pMT-10 mice at days 65 and 90 after infection. (H) Representative hematoxylin and eosin–stained lung sections and percentage of infiltrated area in lungs at 65 days after infection. Individual data points represent individual animals. Data represent 3 independent experiments with 4–5 mice per group. Data area shown as the mean ± SD. **P < 0.01; ***P < 0.001; ***P < 0.0001 by Student’s t test.

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