ABSTRACT Dysregulated Th2 responses are central to the pathogenesis of allergic diseases. The central dogma is that classical dendritic cells (cDCs) are the primary drivers of Th2 cells, this has been largely established using strategies targeting CD11c, which while expressed by cDCs, is also present by other cells like monocytes and macrophages. Our data demonstrates the existence of population of MafB+CD11c+MHCIIhi interstitial macrophages (MHCIIhi IMs), significantly induced in response to house dust mite (HDM). Thus, previous strategies aimed at cDCs may have co-targeted these IMs. Using specific targeting, we show for the first time that these MHCIIhi IMs are central to driving allergen-induced Th2 responses in the airways. Our data propose that the development of Th2 immunity, which has long been the purview of dendritic cells, now includes a central role for MHCIIhi IMs. Consistently, we also find that HLA-DRhi macrophages are elevated in the tissue of patients with allergic nasal polyps. Although their regulation during allergy is not understood. Using chemogenetic approaches, we find that pulmonary innervation emanating from the vagal ganglia (VG) directly induces MHCIIhi IM accumulation during HDM-induced allergic airway inflammation, strongly indicating that VG neurons contribute to IM accumulation in response to allergen. Therefore, vagal ganglion-neuropeptide-IM crosstalk acts as a potential axis mediating airway allergy. Exploring the bioenergetics of these cells, we find that MHCIIhi IMs appear to rely heavily on glucose metabolism for function. They express the highest levels of glycolysis- associated genes, and impairing glucose metabolism decreases their ability to take up HDM, something not seen in cDCs in vivo, suggesting that IMs are intrinsically different than cDCs in their reliance on glycolysis for antigen- presenting function. Further, blocking glycolysis reduces eosinophils, Th2 cells, and IgE, but not neutrophils, cDCs, or IL-13+ILCs. Lastly, we found that HDM-elicited MHCIIhi IMs are also highly enriched for arginase-1, a canonical marker of M2 macs, more so than any other myeloid cell type, including AMs. We postulate that innate cytokines act as microenvironmental signals that condition IMs, favoring the development of Th2 cells. Seeking to understand this mechanism, we found that IMs express high levels of the IL-33 receptor, ST2 and eliminating IL-33 signaling impacts arg1+IMs, but not total IMs. Moreover, we found that neuronal inputs induce ST2 expression, thus sensitizing macs to IL-33. In sum, we hypothesize that HDM-elicited IL-33 promotes an M2-like polarization state, favoring an MHCIIhi IM-T cell dialog that drive Th2 responses. To examine this, we propose to: 1) Examine the neuronal pathways regulating MHCIIhi IM accumulation, 2) Examine the glycolytic program of MHCIIhi IMs, and test its requirement for Th2 responses, 3) test neuropeptide-IL-33 axis that drives alternative MHCIIhi IMs polarization favori...