Bhlhe40 is an essential repressor of IL-10 during <i>Mycobacterium tuberculosis</i> infection

Abstract

The cytokine IL-10 antagonizes pathways that control <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) infection. Nevertheless, the impact of IL-10 during <i>Mtb</i> 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 <i>Il10</i> expression during <i>Mtb</i> infection. Loss of Bhlhe40 in mice results in higher <i>Il10</i> expression, higher bacterial burden, and early susceptibility similar to that observed in mice lacking IFN-γ. Deletion of <i>Il10</i> in <i>Bhlhe40</i>^-/- mice reverses these phenotypes. Bhlhe40 deletion in T cells or CD11c⁺ cells is sufficient to cause susceptibility to <i>Mtb</i> Bhlhe40 represents the first transcription factor found to be essential during <i>Mtb</i> infection to specifically regulate <i>Il10</i> 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 <i>Mtb</i> pathogenesis.