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.
|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|
|URL link to publisher's version||https://www.ncbi.nlm.nih.gov/pubmed/33437483|