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The kinase TAK is required for the development of conventional and regulatory T cells. We previously reported that mice with conditional deletion of TAK1 in T cells (Lck-cre:TAK1 fl/fl  mice) exhibited severe T lymphopenia, and were nevertheless predisposed to spontaneous colitis with unknown etiology. Here we focused on the immunopathological mechanism in colitic Lck-cre:TAK1 fl/fl  mice. We found that ‘leaky’ CD4 +  T cells retaining TAK1 acquired inflammatory phenotypes that contribute to disease onset in Lck-cre:TAK1 fl/fl  mice. Furthermore, the gut microbiota-triggered signaling was also a key event leading to the pathogenesis. We discovered that Lck-cre:TAK1 fl/fl  mice were almost completely devoid of TCRαβ + CD8α +  intestinal intraepithelial lymphocytes (IELs) and this was largely due to the developmental defect of the thymic precursors by TAK1 deficiency. Remarkably, transfer of TCRαβ + CD8α +  IELs from wild-type mice ameliorated colitis in Lck-cre:TAK1 fl/fl  mice. Taken together, our current study highlighted the emerging role of TAK1 in configuring the gut-specialized T cell subset, which regulates mucosal homeostasis under lymphopenic conditions.

Conditional Deletion of TAK1 in T Cells Reveals a Pivotal Role of TCRαβ+ Intraepithelial Lymphocytes in Preventing Lymphopenia-Associated Colitis