Open AccessDOCK8 deficiency diminishes thymic T‐regulatory cell development but not thymic deletion
Author(s) -
Randall Katrina L,
Law Hsei Di,
Ziolkowski Andrew F,
Wirasinha Rushika C,
Goodnow Christopher C,
Daley Stephen R
Publication year - 2021
Publication title -
clinical and translational immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.321
H-Index - 34
ISSN - 2050-0068
DOI - 10.1002/cti2.1236
Subject(s) - thymocyte , biology , foxp3 , t cell receptor , t cell , immunology , transgene , il 2 receptor , regulatory t cell , microbiology and biotechnology , apoptosis , adoptive cell transfer , genetically modified mouse , immune system , biochemistry , gene
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.