The small intestine epithelium exempts Foxp3+ Tregs from their IL-2 requirement for homeostasis and effector function
Praveen Prakhar, Jaylene Alvarez-DelValle, Hilary Keller, Assiatu Crossman, Xuguang Tai, Yoo Kyoung Park, Jung-Hyun Park
Praveen Prakhar, Jaylene Alvarez-DelValle, Hilary Keller, Assiatu Crossman, Xuguang Tai, Yoo Kyoung Park, Jung-Hyun Park
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Research Article Immunology

The small intestine epithelium exempts Foxp3+ Tregs from their IL-2 requirement for homeostasis and effector function

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.

Authors

Praveen Prakhar, Jaylene Alvarez-DelValle, Hilary Keller, Assiatu Crossman, Xuguang Tai, Yoo Kyoung Park, Jung-Hyun Park

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Figure 3

SI IEL-associated features of Foxp3+ Tregs.

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SI IEL-associated features of Foxp3+ Tregs. (A) IL-2 expression in LN an...
(A) IL-2 expression in LN and IEL CD4+ (top) and total T cells (bottom) in LN and IEL populations. Contour plots show staining for intracellular IL-2 in CD4+ and total T cells from the indicated organs upon PMA and ionomycin stimulation. The graph shows the summary of 2 independent experiments with 4 WT mice. (B) Histograms show CCR7 and CCR9 expression on Foxp3-GFP+CD4+ T cells from LN and IELs (top). Graphs show the ΔMFI of CCR7 and CCR9 expression (bottom). Histograms are representative, and the graphs show a summary of 2 independent experiments with a total of 5 Foxp3-GFP reporter mice. (C) Histograms show CD103 and CD69 expression on Foxp3-GFP+CD4+ T cells LN and IELs (top). The graphs show the frequency of CD103+ cells and the ΔMFI of CD69 expression (bottom). Histograms are representative, and the graphs show a summary of 2 independent experiments with a total of 4 Foxp3-GFP reporter mice. (D) IL-10 expression in LN and IEL Foxp3+ Tregs. Contour plots show staining for intracellular IL-10 in Foxp3+ Tregs from the indicated organs upon PMA + ionomycin stimulation (left). The graph shows the summary of 3 independent experiments with 5 Foxp3-GFP reporter mice (right). (E) Treg suppression assays with FACS-sorted Foxp3+ Tregs from LN and IELs of Foxp3-GFP reporter mice. Cell Trace Violet (CTV) dilution was monitored to visualize the proliferation of responder T cells (Tresp) after 5 days of in vitro stimulation in the absence or presence of Tregs at a 1:1 ratio. Data are representative of 2 independent experiments. The data are represented as the mean ± SEM. P values were determined by paired Student’s t test. **P < 0.01, and ***P < 0.001.