Signaling abnormalities in immune responses in the small intestine can trigger chronic type 2 inflammation, involving the interaction of multiple immune cell types. To systematically characterize this response, we analyzed 58,067 immune cells from the mouse small intestine by single-cell RNA-seq (scRNA-seq), at steady-state and after induction of a type 2 inflammatory reaction to ovalbumin (OVA). The analysis revealed broad shifts in both cell-type composition and cell programs in response to the inflammation, especially in group 2 innate lymphoid cells (ILC2s). Among the key transcript characteristics associated with an inflammation-induced program in intestinal KLRG1 + ILC2s was the level of exon 5 of Calca, which encodes the alpha-calcitonin gene-related peptide (α-CGRP). α-CGRP antagonized IL-25-induced activation of intestinal KLRG1 + ILC2s and reduced ILC2 frequency in an OVA reaction model. α-CGRP activated a cyclic AMP (cAMP) response, which suppressed ILC2 proliferation. At homeostasis, α-CGRP was predominantly expressed by two subsets of ChAT + enteric neurons, and genetic perturbation of α-CGRP increased the proportion of intestinal KLRG1 + ILC2s and the number of Tuft cells. Our work highlights a model where α-CGRP-mediated neuronal signaling is critical for suppressing ILC2 expansion and maintaining homeostasis of type 2 immune machinery.