Abstract The skin is a highly innervated organ and contains numerous sensory afferent neurons that respond to a diverse array of stimuli including touch, pruritogens (inducing itch) and noxious agents (inducing pain). There are also many skin-resident immune cells including dendritic cells and mast cells that make direct contact with sensory neurons. It has very recently become appreciated that cutaneous sensory neurons and skin-resident innate immune cells work synergistically to initiate local inflammation and host defense. We have previously shown that TRPV1+ neurons that sense pain are necessary and sufficient for cutaneous innate Type-17 inflammation and host defense against C. albicans. Thus, a neuron subset associated with painful stimuli is necessary and sufficient to drive a Type-17 immune response which is the optimal immune response against extracellular pathogens that can cause painful stimuli. We now propose to test the immunologic potential of nonpeptidergic sensory neurons are that can be divided based on single cell RNAseq into at least 3 subsets: NP1, NP2, and NP3. The overall goal of this proposal is to understand the unique contribution of individual subsets of nonpeptidergic sensory neurons to the modulation of skin immunity. Exploring this neuro- immune interaction will better define the cellular circuits driving inflammation and allow for the use of agonists/antagonists that target neuron subsets in order to modulate specific types of cutaneous immune responses without global immunosuppression. Specifically, we hypothesize that NP1 sensory nerves function to suppress mast cell activity. We further hypothesize that the NP2 and NP3 subsets that communicate itch sensation in response to pruritogens also participate in the development of Type-2 immune responses analogous to TRPV1+ neurons and Type-17 immune responses. The potential to modulate Th2 and mast cell function makes these pathways potential key for allergic disease pathogenesis.