Hematopoietic Antigen Presenting Cells Fine-Tune the Effector Phenotype of Intrathymic Unconventional αβ T Cells

The development of unconventional αβ T cells, including invariant natural killer T (iNKT) and mucosal-associated invariant T (MAIT) cells, in the thymus is distinct from conventional T cells. Unconventional αβ T cells adopt a memory phenotype, acquire effector functions, and can reside in the thymus long-term. It is well-established that positive selection of these unconventional T cells from CD4⁺CD8⁺ double-positive (DP) precursors depends on interaction with other DP cells. However, postselection, the regulation of their maturation and effector differentiation is less well understood. Professional antigen-presenting cells (APCs) are thought to have a role, but their roles have only been partially investigated previously. In this study, we investigate the impact of perturbing thymic dendritic cell (DC) and macrophage populations on intrathymic iNKT and MAIT effector subsets in C57BL/6 mice. We show that conventional type 1 DCs (cDC1s) support iNKT1 cells, while CX3CR1- and Mgl2-expressing cDC2s and macrophages support MAIT17 cells. Lastly, we show that disrupting the XCR1-XCL1 axis, which was previously shown to control cDC1 localization to the thymic cortex, alters the balance between iNKT and MAIT cells in the thymus, where there is augmentation of the iNKT cell compartment at the expense of MAIT cells. These findings further highlight the roles of hematopoietic APCs in supporting intrathymic unconventional αβ T cells.