Thymic Development of a Unique Bone Marrow-Resident Innate-like T Cell Subset with a Potent Innate Immune Function

Mainstream CD8⁺ and CD4⁺ T cells of αβ lineage are developed in the thymus through TCR-mediated selection in the context of MHC class I and MHC class II in association with self-peptides, respectively. In addition, minor αβT cells bearing invariant TCRs, NKT cells, and mucosal-associated invariant T cells are selected via MHC-like molecules, CD1d, and MR1 complexed with nonpeptide Ags, respectively, parts of which express neither CD4 nor CD8. In this study, we indicate that bone marrow (BM), but barely other lymphoid tissues, harbors CD4/CD8 double-negative αβT cells with an apparently diverse TCR repertoire at considerable proportions in healthy adult mice. The BM-resident double-negative αβT (BMDNT) cells are developed in the thymus in a Notch and IL-7-dependent manner but independently of known restriction elements, including MHC class I, MHC class II, CD1d, and MR1. These cells are sustained in BM throughout the adult stage with "homeostatic" proliferation via IL-1β derived from normal myeloid cells dominating the BM environment. Although BMDNT cells secrete a unique set of cytokines, including IL-17, GM-CSF, IL-3, and CCL chemokines on TCR stimulation, these T cells also express a series of NK receptors and exhibit a potent NK-like cytotoxic activity. Furthermore, BMDNT cells show robustly accelerated proliferation and activation following systemic administration of TLR ligands likely through the enhanced production of IL-1β by myeloid cells in situ. Our results suggest that αβT lineage cells that are developed in the thymus by default of TCR-mediated selection are maintained and differentiated to innate-like T cells in BM and may play a role in innate immunity in the hematopoietic environment.