DOCK8 deficiency diminishes thymic T-regulatory cell development but not thymic deletion

Katrina L. Randall*, Hsei Di Law, Andrew F. Ziolkowski, Rushika C. Wirasinha, Christopher C. Goodnow, Stephen R. Daley

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    6 Citations (Scopus)

    Abstract

    Objective: To define the effect of DOCK8 deficiency on thymic tolerance in mice. Methods: Thymocytes from wild-type (Dock8+/+) and DOCK8-deficient (Dock8pri/pri) mice were examined by flow cytometry. Some mice had transgenic expression of the BCL2 anti-apoptotic protein in haemopoietic cells. Some mice expressed the transgenic 3A9 T-cell receptor (TCR), which triggers thymocyte deletion in mice also expressing hen egg lysozyme under the insulin promoter. Results: In Dock8pr/pri mice, the proportion of thymocytes induced to acquire tolerance at the immature CCR7 stage was normal. Deletion of strongly self-reactive CD4+ thymocytes occurred efficiently in Dock8pri/pri mice in a TCR-transgenic model that requires self-antigen transfer from epithelial cells to bone marrow (BM)-derived antigen-presenting cells. Thymic Foxp3+ T-regulatory cells (TREG) and Helios+ Foxp3 TREG precursors were decreased in Dock8pri/pri mice, including when apoptosis was inhibited by BCL2 transgene expression. Dock8pri/pri thymic TREG expressed CD25 and CTLA-4 at normal levels. The results suggest that DOCK8 deficiency does not affect the function of BM-derived antigen-presenting cells in the thymus, the TCR self-reactivity threshold that activates tolerance mechanisms in thymocytes or the apoptotic deletion of these thymocytes. However, DOCK8 is required to prevent a subset of developing TREG cells from undergoing cell death via a mechanism that is distinct from apoptosis. Conclusion: DOCK8 deficiency diminishes TREG development in the thymus without compromising thymocyte deletion.

    Original languageEnglish
    Article numbere1236
    JournalClinical and Translational Immunology
    Volume10
    Issue number1
    DOIs
    Publication statusPublished - 2021

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