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

ABSTRACT: 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. Deleterious mutations in DOCK8 cause a severe immune deficiency syndrome, but whether thymic self?tolerance mechanisms are affected has been unclear. In this study, we found that DOCK8?deficient mice have normal clonal deletion of self?reactive T cells at two stages of development in the thymus. However, DOCK8 deficiency conferred a T?cell?intrinsic defect in the intrathymic differentiation of Foxp3+ T?regulatory cells.

SUBMITTER: Randall K 

PROVIDER: S-EPMC7790591 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature