{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T19:58:34Z","timestamp":1792612714078,"version":"4.5.0"},"reference-count":79,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T00:00:00Z","timestamp":1763424000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010877","name":"Science, Technology and Innovation Commission of Shenzhen Municipality","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100010877","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Calcitonin gene-related peptide (CGRP), a neuropeptide released by sensory neurons, plays an emerging role in immune regulation, yet its function in adaptive immunity remains poorly understood. Here, we identify the CGRP\u2013RAMP1 pathway as a key intrinsic regulator of CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cell responses during allergic sensitization.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      House dust mite (HDM) was used to induce allergic sensitization in mice. CGRP\n                      <jats:sup>+<\/jats:sup>\n                      sensory nerve fiber distribution in mediastinal lymph nodes (medLNs) was analyzed with whole-mount imaging. RAMP1 expression on immune cells was assessed with a RAMP1-mCherry reporter by flow cytometry. TCR-seq, parabiosis, and adoptive transfer were employed to assess the biological roles of RAMP1 expression in CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells.\n                      <jats:italic>In vitro<\/jats:italic>\n                      , CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells were stimulated, differentiated, and analyzed by flow cytometry, ATAC-seq, and RNA-seq to evaluate the impact of CGRP. CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cell-specific RAMP1 knockout mice and CGRP treatment were used to evaluate immune cell infiltration and Tfh responses in allergic sensitization. Additionally,\n                      <jats:italic>\n                        Calca\n                        <jats:sup>\u2212\/\u2212<\/jats:sup>\n                        , Ramp1\n                        <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      <\/jats:italic>\n                      , and CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cell-specific RAMP1 knockout mice were used from immunological studies in the HDM-induced allergic asthma model. CGRP was intraperitoneally injected to evaluate its preventive effect on asthma.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      CGRP\n                      <jats:sup>+<\/jats:sup>\n                      fibers densely innervate medLNs. In CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells, RAMP1 is preferentially expressed on na\u00efve ones. While RAMP1 does not affect thymocyte development, TCR diversity, or tissue residency, CGRP\u2013RAMP1 signaling suppresses CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cell activation and differentiation. CGRP reshapes chromatin accessibility and transcriptional programs to suppress a responsive state and repress Tfh-associated gene expression of CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells. Following allergen sensitization, the density of CGRP\n                      <jats:sup>+<\/jats:sup>\n                      fibers in the medLNs is reduced. CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cell-specific RAMP1 deficiency promotes Tfh cell accumulation and B cell activation in the medLNs, exacerbating allergic sensitization. Conversely, exogenous CGRP treatment mitigates allergic sensitization in a RAMP1-dependent manner. Finally, CGRP treatment during the sensitization phase effectively alleviates allergic asthma.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      These findings suggest a neuroimmune axis in which CGRP\u2013RAMP1 pathway restrains allergic sensitization by directly modulating the immunobiology of CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1671269","type":"journal-article","created":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T14:13:32Z","timestamp":1765808012000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["CGRP restrains CD4+ T cell responses and allergic sensitization"],"prefix":"10.3389","volume":"16","author":[{"given":"Xiaoshi","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenlong","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingren","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ai","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayi","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jialin","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heng","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,11,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0247-z","article-title":"Neuroimmune 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