TLE3 and TLE4-coordinated colonic macrophage-CD4⁺ T cell crosstalk maintains intestinal immune homeostasis

Colonic macrophages are critical for maintenance of cluster of differentiation 4 T helper (CD4⁺ T) cell homeostasis in the intestinal lamina propria. However, the mechanisms by which this process is regulated at the transcriptional level remain unknown. In this study, we found that the transcriptional corepressors transducin-like enhancer of split (TLE)3 and TLE4, but not TLE1 or TLE2, in colonic macrophages controlled homeostasis of CD4⁺ T-cell pool in the colonic lamina propria. Mice lacking TLE3 or TLE4 in myeloid cells exhibited markedly increased numbers of regulatory T (T_reg) and T helper (T_H) 17 cells under homeostatic conditions, rendering them more resistant to experimental colitis. Mechanistically, TLE3 and TLE4 negatively regulated matrix metalloproteinase (Mmp)9 transcription in colonic macrophages. Tle3 or Tle4 deficiency in colonic macrophages resulted in upregulated MMP9 production and thus enhanced latent transforming growth factor-beta (TGF-β) activation, which subsequently led to T_reg and T_H17 cell expansion. These results advanced our knowledge regarding the intricate crosstalk between the intestinal innate and adaptive immune compartments.