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

• Published in: The Journal of experimental medicine Vol. 215; no. 7; pp. 1823 - 1838
• Main Authors: Huynh, Jeremy P., Lin, Chih-Chung, Kimmey, Jacqueline M., Jarjour, Nicholas N., Schwarzkopf, Elizabeth A., Bradstreet, Tara R., Shchukina, Irina, Shpynov, Oleg, Weaver, Casey T., Taneja, Reshma, Artyomov, Maxim N., Edelson, Brian T., Stallings, Christina L.
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 02.07.2018
• Subjects: Adaptive control; Adaptive Immunity; Animal models; Animals; Base Sequence; Basic Helix-Loop-Helix Transcription Factors - deficiency; Basic Helix-Loop-Helix Transcription Factors - metabolism; CD11c antigen; Clonal deletion; Genetic Loci; Helix-loop-helix proteins (basic); Homeodomain Proteins - metabolism; Immune system; Immunity, Innate; Infections; Inflammation - pathology; Interleukin 1; Interleukin 10; Interleukin-10 - deficiency; Interleukin-10 - metabolism; Lymphocytes; Lymphocytes - metabolism; Lymphocytes T; Mice; Mice, Inbred C57BL; Models, Biological; Mycobacterium tuberculosis; Myeloid Cells - metabolism; Neutrophils - metabolism; Pathogenesis; Phenotypes; Protein Binding; Repressor Proteins - metabolism; Th1 Cells - metabolism; Transcription factors; Tuberculosis; Tuberculosis - immunology; Tuberculosis - prevention & control; γ-Interferon
• ISSN: 0022-1007; 1540-9538; 1540-9538
• DOI: 10.1084/jem.20171704

The cytokine IL-10 antagonizes pathways that control Mycobacterium tuberculosis (Mtb) infection. Nevertheless, the impact of IL-10 during Mtb infection has been difficult to decipher because loss-of-function studies in animal models have yielded only mild phenotypes. We have discovered that the transcription factor basic helix-loop-helix family member e40 (Bhlhe40) is required to repress Il10 expression during Mtb infection. Loss of Bhlhe40 in mice results in higher Il10 expression, higher bacterial burden, and early susceptibility similar to that observed in mice lacking IFN-γ. Deletion of Il10 in Bhlhe40−/− mice reverses these phenotypes. Bhlhe40 deletion in T cells or CD11c+ cells is sufficient to cause susceptibility to Mtb. Bhlhe40 represents the first transcription factor found to be essential during Mtb infection to specifically regulate Il10 expression, revealing the importance of strict control of IL-10 production by innate and adaptive immune cells during infection. Our findings uncover a previously elusive but significant role for IL-10 in Mtb pathogenesis.