Differentiation of regulatory Foxp3+ T cells in the thymic cortex

Article (PDF Available)inProceedings of the National Academy of Sciences 105(33):11903-8 · September 2008with47 Reads
DOI: 10.1073/pnas.0801506105 · Source: PubMed
Regulatory Foxp3⁺ T cells (TR) are indispensable for preventing autoimmune pathology in multiple organs and tissues. During thymic differentiation T cell receptor (TCR)–ligand interactions within a certain increased affinity range, in conjunction with γc-containing cytokine receptor signals, induce Foxp3 expression and thereby commit developing thymocytes to the TR lineage. The contribution of distinct MHC class II–expressing accessory cell types to the differentiation process of Foxp3⁺ thymocytes remains controversial, because a unique role in this process has been ascribed to either thymic dendritic cells (tDC) or to medullary thymic epithelial cells (mTEC). Furthermore, it was suggested that the thymic medulla, where the bulk of the negative selection of self-reactive thymocytes takes place, provides a specialized microenvironment supporting TR differentiation. Here, we report that the cortex, as defined by cortical thymic epithelial cells (cTEC), is sufficient for supporting TR differentiation. MHC class II expression restricted to both cTEC and mTEC or to cTEC alone did not significantly affect the numbers of Foxp3⁺ thymocytes. Furthermore, genetic or pharmacologic blockade of thymocyte migration resulted in a prominent accumulation of Foxp3⁺ thymocytes in the cortex, demonstrating that secondary signals required for Foxp3 up-regulation exist in the cortex. Our results suggest that mTEC or tDC do not serve as a cell type singularly responsible for TR differentiation and that neither the cortex nor the medulla exclusively provides an environment suitable for Foxp3 induction. Instead, multiple accessory cell types probably contribute to the thymic generation of regulatory Foxp3⁺ T cells. • immune tolerance • selection • thymus

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    • "Different subsets of stromal cells have been shown to favor tTreg cell development. In a mouse model, it was shown that cortical TECs (cTECs) can be sufficient for tTreg cell differentiation [112]. In humans, plasmacytoid DCs can support tTreg cell differentiation under CD40L and IL-3 activation [113]. "
    [Show abstract] [Hide abstract] ABSTRACT: The most common form of Myasthenia gravis (MG) is due to anti-acetylcholine receptor (AChR) antibodies and is frequently associated with thymic pathology. In this review, we discuss the immunopathological characteristics and molecular mechanisms of thymic follicular hyperplasia, the effects of corticosteroids on this thymic pathology, and the role of thymic epithelial cells (TEC), a key player in the inflammatory thymic mechanisms. This review is based not only on the literature data but also on thymic transcriptome results and analyses of pathological and immunological correlations in a vast cohort of 1035 MG patients without thymoma. We show that among patients presenting a thymic hyperplasia with germinal centers (GC), 80 % are females, indicating that thymic follicular hyperplasia is mainly a disease of women. The presence of anti-AChR antibodies is correlated with the degree of follicular hyperplasia, suggesting that the thymus is a source of anti-AChR antibodies. The degree of hyperplasia is not dependent upon the time from the onset, implying that either the antigen is chronically expressed and/or that the mechanisms of the resolution of the GC are not efficiently controlled. Glucocorticoids, a conventional therapy in MG, induce a significant reduction in the GC number, together with changes in the expression of chemokines and angiogenesis. These changes are likely related to the acetylation molecular process, overrepresented in corticosteroid-treated patients, and essential for gene regulation. Altogether, based on the pathological and molecular thymic abnormalities found in MG patients, this review provides some explanations for the benefit of thymectomy in early-onset MG patients.
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    • "Although pathways in the development of medullary thymic epithelial cells (mTEC) are becoming clearer (Ohigashi et al., 2015;Takaba et al., 2015), the role of the medulla in Treg generation is still poorly understood. Nevertheless , entry into the medulla is known to be triggered by positive selection, with induction of CCR7 expression altering the migratory ability of newly selected thymocytes and enabling access medullary thymic microenvironments (Kwan and Killeen, 2004;Liston et al., 2008;Ueno et al., 2004). In Ccr7 À/À mice, the ability of conventional thymocytes to enter the medulla is dramatically altered, fitting well with their reported breakdown in negative selection (Davalos-Misslitz et al., 2007;Kurobe et al., 2006;Nitta et al., 2009). "
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