Type 2 cytokines in the thymus activate Sirpα+ dendritic cells to promote clonal deletion

Breed et al. identify a subset of thymic SIRP alpha(+) cDC2 dendritic cells that express CD301b, induced by type II cytokines, and high amounts of MHC-II. They find that the deletion of these cells can alter thymic CD4-single-positive repertoires, suggesting that they contribute to thymic tolerance. The thymus contains a diversity of dendritic cells (DCs) that exist in defined locations and have different antigen-processing and -presenting features. This suggests that they play nonredundant roles in mediating thymocyte selection. In an effort to eliminate SIRP alpha(+) classic DC2 subsets, we discovered that a substantial proportion expresses the surface lectin, CD301b, in the thymus. These cells resemble the CD301b(+) type 2 immune response promoting DCs that are present in the skin-draining lymph nodes. Transcriptional and phenotypic comparison to other DC subsets in the thymus revealed that thymic CD301b(+) cDCs represent an activated state that exhibits enhanced antigen processing and presentation. Furthermore, a CD301b(+) cDC2 subset demonstrated a type 2 cytokine signature and required steady-state interleukin-4 receptor signaling. Selective ablation of CD301b(+) cDC2 subsets impaired clonal deletion without affecting regulatory T cells (T-reg cells). The T cell receptor alpha repertoire sequencing confirmed that a cDC2 subset promotes deletion of conventional T cells with minimal effect on T-reg cell selection. Together, these findings suggest that cytokine-induced activation of DCs in the thymus substantially enforces central tolerance.