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 (T-REG) and Helios(+) Foxp3(-) T-REG precursors were decreased in Dock8(pri/pri) mice, including when apoptosis was inhibited by BCL2 transgene expression. Dock8(pri/pri) thymic T-REG 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 T-REG cells from undergoing cell death via a mechanism that is distinct from apoptosis. Conclusion. DOCK8 deficiency diminishes T-REG development in the thymus without compromising thymocyte deletion.

Automated summary

DOCK8 deficiency impairs T-REG development in the thymus without compromising thymocyte deletion.