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


Objective: To define the effect of DOCK8 deficiency on thymic tolerance in mice. Methods: Thymocytes from wild-type (Dock8(+/+) ) and DOCK8-deficient (Dock8(pri/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 Dock8(pr/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 Dock8(pri/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 Dock8(pri/pri) mice, including when apoptosis was inhibited by BCL2 transgene expression. Dock8(pri/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.

Type Journal
ISBN 2050-0068 (Print) 2050-0068 (Linking)
Authors Randall, K. L.; Law, H. D.; Ziolkowski, A. F.; Wirasinha, R. C.; Goodnow, C. C.; Daley, S. R.
Responsible Garvan Author Prof Christopher Goodnow
Publisher Name Clinical & Translational Immunology
Published Date 2021-01-31
Published Volume 10
Published Issue 1
Published Pages e1236
Status Published in-print
DOI 10.1002/cti2.1236
URL link to publisher's version