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.

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Fig. 1: Heightened immune sensitivity to common allergens in early life.

Fig. 2: Type 17 immunity drives early-life responses to HDM.

Fig. 3: pii-DCs trigger HDM skin inflammation in early life.

Fig. 4: pii-cDC2-derived IL-23 activates γδ T17 cells directly in pup skin after HDM exposure.

Fig. 5: Developing HPA and low systemic corticosterone levels in early life enable the pii-DC state.

Peripheral immune-inducer dendritic cells drive early-life allergic inflammation

Peripheral immune-inducer dendritic cells drive early-life allergic inflammation

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