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

Elise R Breed, Matouš Vobořil, Katherine M Ashby, Ryan J Martinez, Lily Qian, Haiguang Wang, Oscar C. Salgado, Christine H. O’Connor, Kristin A. Hogquist

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

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 SIRPα+ 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 (Treg cells). The T cell receptor α repertoire sequencing confirmed that a cDC2 subset promotes deletion of conventional T cells with minimal effect on Treg cell selection. Together, these findings suggest that cytokine-induced activation of DCs in the thymus substantially enforces central tolerance.

Original languageEnglish (US)
Pages (from-to)1042-1051
Number of pages10
JournalNature immunology
Volume23
Issue number7
DOIs
StatePublished - Jul 2022

Bibliographical note

Funding Information:
We thank J. Ding for technical assistance, J. Motl from the University Flow Cytometry Resource for cell sorting, T. Dileepan for providing tetramer reagents, the University of Minnesota Genomics Center for assistance with RNA-seq and the University of Minnesota Research Animal Resources for animal husbandry. This project was supported by the National Institutes of Health (grant nos. R37 AI39560 and P01 AI35296 to K.A.H., T32 AI007313 to K.M.A. and E.R.B., and F30 AI131483 and T32 GM008244 to E.R.B.).

Funding Information:
We thank J. Ding for technical assistance, J. Motl from the University Flow Cytometry Resource for cell sorting, T. Dileepan for providing tetramer reagents, the University of Minnesota Genomics Center for assistance with RNA-seq and the University of Minnesota Research Animal Resources for animal husbandry. This project was supported by the National Institutes of Health (grant nos. R37 AI39560 and P01 AI35296 to K.A.H., T32 AI007313 to K.M.A. and E.R.B., and F30 AI131483 and T32 GM008244 to E.R.B.).

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.

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