Abstract The somatosensory nervous system surveils external stimuli at barrier tissues, regulating innate immune cells under infection and inflammation. The roles of nociceptive nerves in homeostatic adaptive immunity to the microbiota, however, remain elusive. Here, we identified a novel mechanism for direct neuro-immune interaction between commensal-specific T lymphocytes and skin-innervating nociceptive neurons through secretion of calcitonin gene-related peptide (CGRP). We observed upregulation of the CGRP co-receptor, receptor activity modifying protein 1 (RAMP1), in T lymphocytes induced by topical colonization of the human skin commensal Staphylococcus epidermidis, but not in T cell populations elicited by cutaneous infection or inflammation. Utilizing intravital imaging, we observed that commensal-specific T cells interact intimately and dynamically with skin nociceptive nerves in a CGRP-dependent manner. Importantly, CGRP secreted from nociceptors acts directly on commensal-specific T cells via RAMP1 to regulate their accumulation in the tissues, cytokine production and motility in vivo. Activation or inhibition of nociceptive neurons functionally tune commensal-specific T cells and optimize their responses to ensuing heterologous infections or damaging challenges in the skin. The ability of the somatosensory neurons to participate in the highly specific and potentially long-lasting adaptive immune response to the microbiota underscores the functional versatility and plasticity of commensal-specific T lymphocytes that can be swiftly tuned to diverse arrays of sensory modalities ranging from thermosensation to noxious pain under steady state and pathology. Supported by Damon Runyon Cancer Research Foundation