Abstract
Foxp3+ Tregs are potent immunosuppressive CD4+ T cells that are critical to maintain immune quiescence and prevent autoimmunity. Both the generation and maintenance of Foxp3+ Tregs depend on the cytokine IL-2. Hence, the expression of the IL-2 receptor α-chain (CD25) is not only considered a specific marker, but also a nonredundant requirement for Tregs. Here, we report that Foxp3+ Tregs in the small intestine (SI) epithelium, a critical barrier tissue, are exempt from such an IL-2 requirement, since they had dramatically downregulated CD25 expression, showed minimal STAT5 phosphorylation ex vivo, and were unable to respond to IL-2 in vitro. Nonetheless, SI epithelial Tregs survived and were present at the same frequency as in other lymphoid organs, and they retained potent suppressor function that was associated with high levels of CTLA-4 expression and the production of copious amounts of IL-10. Moreover, adoptive transfer experiments of Foxp3+ Tregs revealed that such IL-2–independent survival and effector functions were imposed by the SI epithelial tissue, suggesting that tissue adaptation is a mechanism that tailors the effector function and survival requirements of Foxp3+ Tregs specific to the tissue environment.
Highlights
CD4+ T cells that express the transcription factor Foxp3 are commonly referred to as Tregs, and such Foxp3+ Tregs play nonredundant roles in maintaining the immune quiescence in peripheral tissues [1]
We report that Foxp3+ Tregs in the small intestine (SI) epithelium, a critical barrier tissue, are exempt from such an IL-2 requirement, since they had dramatically downregulated CD25 expression, showed minimal STAT5 phosphorylation ex vivo, and were unable to respond to IL-2 in vitro
We found that the frequency of Foxp3+CD4+ T cells did not significantly differ between lymph node (LN) and intraepithelial lymphocytes (IELs) (Figure 1A)
Summary
CD4+ T cells that express the transcription factor Foxp are commonly referred to as Tregs, and such Foxp3+ Tregs play nonredundant roles in maintaining the immune quiescence in peripheral tissues [1]. Foxp3+ Tregs comprise a phenotypically and functionally diverse population, and they express a range of different effector molecules and surface markers, which has led to the identification of multiple Treg subsets [2]. Whether these different subsets correspond to terminally differentiated effector cells or whether plasticity remains among the distinct subsets is not fully resolved. To further complicate this issue, Foxp3+ Tregs are generated in the thymus, but they can develop from naive CD4+ T cells in peripheral organs [3]. Molecular markers that can differentiate the developmental history of peripheral Tregs are not yet fully established [2]
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