The study investigates the site-specific regulation of Th2 differentiation within lymph node (LN) microenvironments following cutaneous allergen administration. Using quantitative imaging, the authors observed extensive activation and "macro-clustering" of early Th2 cells with migratory type-2 dendritic cells (cDC2s), creating specialized Th2-promoting microenvironments. This macro-clustering was integrin-mediated and promoted localized cytokine exchange among T cells, enhancing T cell activation and differentiation. Surprisingly, the formation of Th2 macro-clusters was dependent on the site of skin sensitization, with differences driven by divergent activation states of cDC2s from different dermal tissues. Enhanced costimulatory molecule expression by cDC2s in Th2-generating LNs promoted prolonged T cell activation, macro-clustering, and cytokine sensing, leading to Th2 differentiation. These findings highlight the importance of enhanced costimulatory molecule signaling in generating dedicated Th2 priming microenvironments and suggest that the generation of T cell responses is heavily influenced by upstream barrier tissues.The study investigates the site-specific regulation of Th2 differentiation within lymph node (LN) microenvironments following cutaneous allergen administration. Using quantitative imaging, the authors observed extensive activation and "macro-clustering" of early Th2 cells with migratory type-2 dendritic cells (cDC2s), creating specialized Th2-promoting microenvironments. This macro-clustering was integrin-mediated and promoted localized cytokine exchange among T cells, enhancing T cell activation and differentiation. Surprisingly, the formation of Th2 macro-clusters was dependent on the site of skin sensitization, with differences driven by divergent activation states of cDC2s from different dermal tissues. Enhanced costimulatory molecule expression by cDC2s in Th2-generating LNs promoted prolonged T cell activation, macro-clustering, and cytokine sensing, leading to Th2 differentiation. These findings highlight the importance of enhanced costimulatory molecule signaling in generating dedicated Th2 priming microenvironments and suggest that the generation of T cell responses is heavily influenced by upstream barrier tissues.