CGRP-RAMP1 Negatively Regulates CD4⁺ T Cell Responses to Suppress Allergic Asthma

Calcitonin gene-related peptide (CGRP) is a neuropeptide released from sensory neurons that, similarly with CD4⁺ T cells, are essential for asthmatic hyperreactivity. CGRP acts via a heterodimeric receptor composed of CALCRL and RAMP1 on immune cells such as ILC2. However, whether CGRP regulates asthmatic inflammation by acting immune cells is yet to know. Using Ramp1^mCherry mice we first find that 96% of CD62L⁺CD44^- naïve and 23% of CD62L^-CD44⁺ effector CD4⁺ T cells express RAMP1 in the spleen. We next find CGRP or RAMP1 deficiency aggravates house dust mite (HDM)-induced asthma. Furthermore, allergic inflammation and mucus production are exacerbated in Cd4^CreRamp1^fl/fl mice as demonstrated by increased amounts of alveolar eosinophils, B cells and CD4⁺ T effectors, and interstitial CD4⁺ T cells with a higher GATA-3/T-bet ratio. Interestingly, splenic naïve CD4⁺ T cells downregulate their RAMP1 expression during proliferation when activated in vitro.  Mechanistically, the amount of follicular helper CD4⁺ T cell (Tfh) is augmented in Cd4^CreRamp1^fl/fl mice after HDM sensitization. Systemic CGRP treatment during HDM sensitization relieves airway inflammation. Likewise, CGRP potently inhibits CD4⁺ T cell survival, proliferation, CD25 expression, and cytokines release, including IL-2, IL-5, IL-10 and IL-13 in a RAMP1-dependent manner. Our data shed light on the suppressive effect of CGRP on allergic asthma by regulating CD4⁺ T cell activities.