Abstract
The suppressor of cytokine signaling 3 (SOCS3) is a major regulator of immune responses and inflammation as it negatively regulates cytokine signaling. Here, the role of SOCS3 in thymic T cell formation was studied in Socs3fl/fl Actin-creER mice (Δsocs3) with a tamoxifen inducible and ubiquitous Socs3 deficiency. Δsocs3 thymi showed a 90% loss of cellularity and altered cortico-medullary organization. Thymocyte differentiation and proliferation was impaired at the early double negative (CD4-CD8-) cell stage and apoptosis was increased during the double positive (CD4+CD8+) cell stage, resulting in the reduction of recent thymic emigrants in peripheral organs. Using bone marrow chimeras, transplanting thymic organoids and using mice deficient of SOCS3 in thymocytes we found that expression in thymic stromal cells rather than in thymocytes was critical for T cell development. We found that SOCS3 in thymic epithelial cells (TECs) binds to the E3 ubiquitin ligase TRIM 21 and that Trim21−/− mice showed increased thymic cellularity. Δsocs3 TECs showed alterations in the expression of genes involved in positive and negative selection and lympho-stromal interactions. SOCS3-dependent signal inhibition of the common gp130 subunit of the IL-6 receptor family was redundant for T cell formation. Together, SOCS3 expression in thymic stroma cells is critical for T cell development and for maintenance of thymus architecture.
Highlights
The function of the thymus is to generate T lymphocytes that express T cell receptors with sufficient diversity to combat different microorganisms and tumors, while eradicating potentially autoreactive T cells
suppressor of cytokine signaling 3 (SOCS3) Is Required for Maintenance of Thymus Structure and Thymocyte Differentiation
In order to study the role of SOCS3 in the production of T cells in the thymus, socs3 mice were treated with tamoxifen (Tm) for 5 days
Summary
The function of the thymus is to generate T lymphocytes that express T cell receptors with sufficient diversity to combat different microorganisms and tumors, while eradicating potentially autoreactive T cells. The thymus is histologically structured into discrete peripheral cortical and central medullary regions. These regions contain distinct stromal cell populations where thymic epithelial cells (TECs) are the main cell type, as well as immature T cells referred as thymocytes at defined stages of maturation. Diverse subsets of TECs in the cortex (cTECs) and medulla (mTECs) provide signals required for the survival and differentiation of thymocytes. The stepwise progression of thymocyte development requires their migration through these thymic regions, where interactions with cTEC and mTEC subsets take place [1].
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