Nutrient-derived signals regulate eosinophil adaptation to the small intestine

Eosinophils are commonly regarded as effector cells of type 2 immunity, yet they also accumulate in certain tissues during homeostasis - particularly in the gastrointestinal tract. Our understanding of the processes that govern homeostatic eosinophil accumulation and tissue-specific adaptation, and their functional significance, remains very limited. Here, we investigated how eosinophils adapt to the small intestine microenvironment and the local signals that regulate this process. We observed that eosinophils gradually migrate up the crypt-villus axis, giving rise to a villus-resident subpopulation with a distinct transcriptional signature. Genetic deficiency of eosinophils resulted in a reduction of villus area, as well as a reduction of multiple other immune cell populations, demonstrating their diverse functions in this environment. We determined that retinoic acid receptor signaling is specifically required for the maintenance of villus-resident eosinophils, while IL-5 is largely dispensable outside of its canonical role in eosinophil production. In addition, we unexpectedly found that high protein diet suppresses 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 not due to altered development in the bone marrow. Our study provides new insight into the process of eosinophil adaptation to the small intestine and its dependence on nutrient-derived signals. Overall design: Small intestine eosinophil populations (a4b7+, a4b7- CD22-, and CD22+) from wild type female B6 mice were isolated by FACS and their transcriptomes were analyzed by RNA-Seq (4 biological replicates per condition)