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

• Published in: The Journal of experimental medicine 2018-07, Vol.215 (7), p.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: Article
• Language: English
• 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
• DOI: 10.1084/jem.20171704

The cytokine IL-10 antagonizes pathways that control ( ) infection. Nevertheless, the impact of IL-10 during 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 expression during infection. Loss of Bhlhe40 in mice results in higher expression, higher bacterial burden, and early susceptibility similar to that observed in mice lacking IFN-γ. Deletion of in mice reverses these phenotypes. Bhlhe40 deletion in T cells or CD11c cells is sufficient to cause susceptibility to Bhlhe40 represents the first transcription factor found to be essential during infection to specifically regulate 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 pathogenesis.