DOCK8 deficiency diminishes thymic T-regulatory cell development but not thymic deletion.
Clin Transl Immunology
; 10(1): e1236, 2021.
Article
em En
| MEDLINE
| ID: mdl-33437483
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.
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Base de dados:
MEDLINE
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article