Interleukin-7 promotes human regulatory T cell development at the CD4+CD8+ double-positive thymocyte stage

Abstract

Although mature human FOXP3(+) regulatory T cells are CD127 (IL-7Rα) negative, CD4(+)CD8(+) FOXP3(+) thymocytes express relatively high levels of CD127 and are responsive to IL-7. However, the role of IL-7 in human regulatory T cell development is poorly known. We show that at the CD4(+)CD8(+) stage, FOXP3(+) thymocytes are highly susceptible to apoptosis, and IL-7 selectively rescues them from death, leading to an increased frequency of FOXP3(+) cells. IL-7 also promotes the development of regulatory T cell phenotype by inducing up-regulation of FOXP3(+) and CTLA-4 expression. In contrast, IL-7 does not enhance proliferation of FOXP3(+)thymocytes or induce demethylation of FOXP3(+) regulatory T cell-specific demethylated region. After the CD4(+)CD8(+) stage, the FOXP3(+) thymocytes down-regulate CD127 expression but despite very low levels of CD127, remain responsive to IL-7. These results suggest that IL-7 affects human regulatory T cell development in the thymus by at least 2 distinct mechanisms: suppression of apoptosis and up-regulation of FOXP3(+) expression.

Effect of Yogurt With or Without Probiotic Addition on Body Composition Changes and Immune System in an Obese Model

“…Figure 2 show representative pictures of the different groups analyzed. The stimulation observed could be due to the production of IL-7 which is involved in the ontogeny and maturation of T lymphocytes [26][27][28]. These studies confirm that yogurt supplementation not only improves thymus weight as we mentioned before, but also significantly improves the histology of this organ (Figure 2).…”

Common gamma chain cytokines promote regulatory T cell development and survival at the CD4+ CD8+ stage in the human thymus

“…We have previously shown that IL‐7 protects DP CD25 + thymocytes from apoptosis, and analysis of Annexin V/propidium iodide staining showed that IL‐2 has the same effect, as well. In these experiments, the surface marker CD25 instead of FOXP3 was used, since permeabilization of the cells is not compatible with detection of apoptotic cells.…”

“…We have previously reported that IL‐7 promotes the Treg phenotype and protects FOXP3 + cells from apoptosis at the DP stage in the human thymus . To see whether the effects of IL‐7 on BCL‐2 were similar to IL‐2, we analysed BCL‐2 expression in the thymocyte culture with and without IL‐7.…”

“…Thus, despite the small size of the FOXP3 + DP population, it is likely that it represents a crucial stage in the development of human natural Tregs. We and others have previously reported that IL‐7 is an important promoter of Treg development, while a recent study identified IL‐2 and IL‐15 as key cytokines for Treg proliferation and survival in the thymus . In the present study, we have investigated the effects of IL‐2, IL‐7 and IL‐15 on the critical FOXP3 + DP population.…”

“…Their development in the thymus has been extensively studied in murine models . Based on these studies, the prevalent view holds that commitment to the Treg lineage takes place at the CD4 + single‐positive (SP) stage, but the existing evidence in humans suggests an earlier point of divergence …”