T Cell–Derived IL-10 Impairs Host Resistance to Mycobacterium tuberculosis Infection

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis infection, is a leading cause of mortality and morbidity, causing ∼1.5 million deaths annually. CD4+ T cells and several cytokines, such as the Th1 cytokine IFN-γ, are critical in the control of this infection. Conversely, the immunosuppressive cytokine IL-10 has been shown to dampen Th1 cell responses to M. tuberculosis infection impairing bacterial clearance. However, the critical cellular source of IL-10 during M. tuberculosis infection is still unknown. Using IL-10 reporter mice, we show in this article that during the first 14 d of M. tuberculosis infection, the predominant cells expressing IL-10 in the lung were Ly6C+ monocytes. However, after day 21 postinfection, IL-10–expressing T cells were also highly represented. Notably, mice deficient in T cell–derived IL-10, but not mice deficient in monocyte-derived IL-10, showed a significant reduction in lung bacterial loads during chronic M. tuberculosis infection compared with fully IL-10–competent mice, indicating a major role for T cell–derived IL-10 in TB susceptibility. IL-10–expressing cells were detected among both CD4+ and CD8+ T cells, expressed high levels of CD44 and Tbet, and were able to coproduce IFN-γ and IL-10 upon ex vivo stimulation. Furthermore, during M. tuberculosis infection, Il10 expression in CD4+ T cells was partially regulated by both IL-27 and type I IFN signaling. Together, our data reveal that, despite the multiple immune sources of IL-10 during M. tuberculosis infection, activated effector T cells are the major source accounting for IL-10–induced TB susceptibility.

Bhlhe40 is an essential repressor of IL-10 during Mycobacterium tuberculosis infection

“…The delay in susceptibility of most of the Bhlhe40 fl/fl -Cd11c-Cre and Bhlhe40 fl/fl -Cd4-Cre mice as compared with Bhlhe40 −/− mice could indicate that the susceptibility of Bhlhe40 −/− mice is a result of the combination of loss of Bhlhe40 in both CD11c + and T cells, insufficient ability of the Cd11c and Cd4 promoters to drive Bhlhe40 exon deletion in all Cre-expressing cells, or the ability of Bhlhe40 deficiency in a non-CD11c + or -CD4 + cell type to enhance susceptibility. IL-10 production by T cells and CD11c + cells during Mtb infection in mice was recently shown to contribute to host susceptibility (Moreira-Teixeira et al, 2017), further supporting the notion that regulation of Il10 expression in these cell populations would be important during Mtb infection.…”

“…Data are from one (A) or two (B-G) independent experiments. sources of IL-10 before and after Mtb infection (Moreira-Teixeira et al, 2017). We crossed 10BiT and Bhlhe40 −/− mice to generate a Bhlhe40 −/− 10BiT-positive strain, and then we analyzed Thy1.1 expression as a proxy for Il10 expression.…”

Mechanisms of M. tuberculosis Immune Evasion as Challenges to TB Vaccine Design

“…T reg contract later and do not accumulate in the lungs of M. tuberculosis -infected mice (Shafiani et al, 2013). Likewise, the immunosuppressive cytokine IL-10 is expressed by myeloid cells and T cells during M. tuberculosis infection, and T cell-derived IL-10 limits control of bacteria in the lungs (Moreira-Teixeira et al, 2017). Blockade of IL-10 receptor signaling during BCG vaccination of mice enhances IL-17 and IFNγ responses by T cells and innate lymphoid cells and improves control of M. tuberculosis (Pitt et al, 2012).…”

Mycobacterium avium subsp. paratuberculosis MAP1889c Protein Induces Maturation of Dendritic Cells and Drives Th2-Biased Immune Responses

“…IL-10 has been shown to interfere with Th1 cell and macrophage function, and IL-10 deficiency improves the outcome of Mtb infection, mainly due to enhanced macrophage and Th1 responses [46,47]. Therefore, hypersecretion of IL-10 provides a niche for the continued survival of pathogens in vitro and in vivo [11,48].…”