CGRP-ramp1 signaling tunes memory CD8 T cell responses through langerhans cells

Summary: Abstract Body: Vaccinia virus (VACV) immunization using a bifurcated needle provides complete protection against Variola major, the causative agent of smallpox, and a vaccination campaign based on this strategy led to the worldwide eradication of smallpox as a disease. CD8+ T cells have a critical role in antiviral immunity in target epithelial tissues. Using a cutaneous VACV infection model, we demonstrate that VACV immunization by skin scarification (s.s.) protects mice more effectively against lethal respiratory challenge than other routes of delivery including intramuscular (i.m.). The skin is innervated by an extensive network of low- and high-threshold sensory nerves, including nociceptive sensory neurons which specialize in detecting noxious stimuli and eliciting pain perception. We found that immunization s.s. with VACV activates Trpv1+ pain fibers and induces pain in mice. However, the role of this phenomenon in shaping CD8 T cell immune responses remains unknown. Here, we show that VACV immunization through s.s. promotes release of the neuropeptide calcitonin gene-related peptide (CGRP) in the skin. Moreover, in the absence of Trpv1+ neurons which are involved in pain perception and the main producer of CGRP, the CD8 T cell response is significantly blunted during both the primary effector and memory phases. By using Kaede X Trpv1-DTA mice, we further show that Langerhans cells (LCs) are critical cellular mediators that respond to CGRP-Ramp1 signaling during VACV immunization. This signaling facilitates their migration from epidermis to draining lymph nodes (dLNs) after s.s. immunization, where they prime antigen specific naïve CD8 T cells. Our findings thus reveals an unanticipated crosstalk between sensory neurons, LCs, and memory CD8 T cells during VACV s.s. immunization, suggesting the potential for enhancing CGRP-Ramp1 signaling to improve vaccine efficacy. Jiang Zhang¹, Jason B. Williams¹, Timothy Pan¹, Alexander Kley¹, Marine A. Lefevre¹, Bharat Rajmalani¹, Liwen Deng², Qian Zhan¹, Rachael A. Clark¹, Isaac M. Chiu², Thomas S. Kupper¹ 1. Department of Dermatology, Brigham and Women's Hospital, Boston, MA, United States. 2. Department of Immunology, Harvard Medical School, Boston, MA, United States. Adaptive and Auto-Immunity