Because of the exposed localization of the olfactory mucosa (OM) to environmental factors, it has to provide the ability to neutralize pathogens and prevent their invasion. Misregulation of the immune response in the OM, like chronic inflammation, was shown to result in an overreacting, horizontal basal cell (HBC) driven, inflammation with subsequent loss of neurons (Chen et al. 2019). Furthermore, it was recently shown that the long-lasting smell loss after SARS-CoV-2 infection might be caused by a persistent inflammation of the OM (Finlay et al. 2022). By using a conditional knockout (cKO) mouse model for the atypical chemokine receptor 3 (ACKR3) in the sustentacular cells (SCs), we demonstrate that SC expressed ACKR3 regulates the local immune response of the OM. ACKR3 is known to trigger β-arrestin signaling and controls migration of leucocytes by scavenging chemokines, but nothing is known about its immune regulating function in the OM. Differential expression analysis of total OM transcriptomic data shows a significant increase of immune related genes in ACKR3 cKO mice. Matching these genes to a public single-cell RNA sequencing data set of the OM (Wang et al. 2022) reveals a major localization of the upregulated transcripts in leucocytes located in the lamina propria. Interestingly, some of the immune related genes are also referring to cell types of the olfactory epithelium like HBCs, SCs and bowman glands. Additional immunofluorescence experiments show a significant increase of leucocyte invasion into the OM, confirming the results of the differential expression analysis. The transcriptomic data, along with immunofluorescence experiments, demonstrate the relevance of SC expressed ACKR3 on the regulation of the immune response of the OM.