Differentiation of regulatory Foxp3⁺T cells in the thymic cortex

Abstract

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 ␥c-containing cytokine receptor signals, induce Foxp3 expression and thereby commit developing thymocytes to the T R 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 T R differentiation. Here, we report that the cortex, as defined by cortical thymic epithelial cells (cTEC), is sufficient for supporting T R 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 T R 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

Differentiation of human thymic regulatory T cells at the double positive stage

“…In agreement, it was recently suggested that human Treg-cell progenitors may selectively reside within mature DP thymocytes expressing high levels of CD69 and TCR-ab, since these cells develop into CD4SP Treg cells in response to activated . Recent murine studies have also demonstrated the possibility of Treg-cell generation in the cortex, followed by rapid migration into the medulla, where they mature [44,45].In conclusion, our data support a model in which significant induction of FOXP3 occurs at the DP stage, prior to CD4 1 or CD8 1 lineage commitment, in the human thymus. FOXP3 1 DP thymocytes were shown to express an activated phenotype that is reminiscent of that found in peripheral activated Treg cells but is associated with the expression of a functional IL-7 receptor, which may serve to protect them from cell death/negative selection.…”

“…The numerical difference in those populations may be explained by a significant commitment to the Treg-cell lineage at the DP stage together with an accumulation of FOXP3 1 SP cells prior to their exit, due to the time-lag incurred by maturation of cells in the thymic medulla [43]. Recent murine studies have also demonstrated the possibility of Treg-cell generation in the cortex, followed by rapid migration into the medulla, where they mature [44,45].…”

“…In agreement, it was recently suggested that human Treg-cell progenitors may selectively reside within mature DP thymocytes expressing high levels of CD69 and TCR-ab, since these cells develop into CD4SP Treg cells in response to activated . Recent murine studies have also demonstrated the possibility of Treg-cell generation in the cortex, followed by rapid migration into the medulla, where they mature [44,45].…”

Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance

“…However, as it will be discussed later on, T cells that express two TCRs on the cell surface may increase the chance of development of autoimmune diseases, thus the significance of receptor editing in establishing tolerance to self is questionable. Furthermore, two studies have implicated cTEC as mediators of dominant tolerance induction 71,72 Furthermore, in our hands K14 driven expression of a transgene led to a detectable expression of protein in mTEC (unpublished observation).…”

A Role for Intrathymic B Cells in the Generation of Natural Regulatory T Cells

“…The thymus harbors a network of APCs including cortical TECs, mTECs, and DCs. Evidence indicates these cells could act coordinately to control T cell development, as deletion of MHC II from either B.M.-derived cells or thymic epithelial cells still allows Treg development (41,48,49). The question remains whether the diverse range of intrathymic APCs make individual and specific contributions to the development of Tregs with unique specificities (47).…”