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

<div><p>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.</p>