| Author |
Xing Y, Reznikov I, Ahmed AN, Sidhu I, Wisnewski J, Farhat A, Prystupa A, Konieczny P, Mansfield K, Cooper ML, Yeung ST, Kim M, Adeghe S, Gaines KD, Manson M, Sim JH, Huang Q, Moshiri AS, Khanna KM, Lu TT, Guttman-Yassky E, Lund AW, Anandasabapathy N, Naik S.
|
| Abstract |
Atopic diseases associated with allergens, as well as allergic diseases, frequently arise early in life; however, the age-dependent mechanisms governing immune responses to allergens remain poorly understood1. Here we find that in early life, exposure to common allergens triggers a distinct bifurcated immune response, simultaneously triggering type 17 inflammation in the skin and initiating canonical T helper 2 sensitization in the lymph nodes. This early-life γδ type 17-mediated dermatitis primes the exaggerated allergic lung inflammation upon secondary allergen exposure. Mechanistically, we find dendritic cell (DC)-mediated type 17 activation directly in the skin without requiring migration to lymph nodes; we term this state 'peripheral immune inducer' (pii) DC. CD301b+ conventional type 2 DCs acquire allergen, adopt the pii-DC state, produce IL-23 and activate local γδ type 17 cells independently of lymph-node engagement. The pii-DC state is enabled by the immature hypothalamic-pituitary-adrenal axis and physiologically low systemic glucocorticoids characteristic of early life2,3; DC-specific deletion of the glucocorticoid receptor recapitulates the pii-DC phenotype. These findings define a developmental checkpoint, set by neuroendocrine maturation, that enables in situ DC activation and immune induction, thereby shaping age-dependent responses to allergens.
|
