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Eosinophils are well recognized as effector cells of type 2 immunity, yet they also accumulate in many tissues under homeostatic conditions. However, the processes that govern homeostatic eosinophil accumulation and tissue-specific adaptation, and their functional significance, remain poorly defined. Here, we investigated how eosinophils adapt to the small intestine (SI) microenvironment and the local signals that regulate this process. We observed that eosinophils gradually migrate along the crypt-villus axis, giving rise to a villus-resident subpopulation with a distinct transcriptional signature. Retinoic acid signaling was specifically required for maintenance of this subpopulation, while IL-5 was largely dispensable outside of its canonical role in eosinophil production. Surprisingly, we found that a high-protein diet suppressed the accumulation of villus-resident eosinophils. Purified amino acids were sufficient for this effect, which was a consequence of accelerated eosinophil turnover within the tissue microenvironment and was not due to altered development in the bone marrow. Our study provides insight into the process of eosinophil adaptation to the SI, highlighting its reliance on nutrient-derived signals. [ABSTRACT FROM AUTHOR]

Interleukin (IL)-21 is a γc-dependent cytokine produced by activated T cells with important actions for T, B, and NK cells. The IL-21 gene is adjacent to the IL-2 gene, and like IL-2, IL-21 is strongly induced at the transcriptional level after T cell activation. Interestingly, however, in contrast to the IL-2 gene, a calcium ionophore alone was sufficient to induce IL-21 gene expression in preactivated T cells. Two DNase I hypersensitivity sites were found in the IL-21 gene, corresponding to nucleotide sequences that are conserved in humans and mice. One site is located at the IL-21 promoter region and conferred T cell receptor-mediated IL-21 gene transcription. TCR-induced IL-21 gene expression was inhibited by cyclosporin A and FK506. Correspondingly, the IL-21 5'-regulatory region contains three NFAT binding sites, and induction of IL-21 promoter activity was impaired when these sites were mutated or following treatment with cyclosporin A. Thus, our studies reveal that in contrast to IL-2, a calcium signal alone is sufficient to mediate induction of the IL-21 in preactivated T lymphocytes and that this induction appears to result from specific NFAT binding. [ABSTRACT FROM AUTHOR]