Th2 responses protect against pathogens but can also cause allergic inflammation. This study investigates how Th2 differentiation occurs in lymph nodes (LNs) after cutaneous allergen exposure. Using quantitative imaging, the researchers found that early Th2 cells form "macro-clusters" with migratory type-2 dendritic cells (cDC2s), creating specialized Th2-promoting microenvironments. These clusters are integrin-mediated and enhance cytokine exchange, promoting Th2 differentiation. This behavior contrasts with Th1 responses. The formation of Th2 macro-clusters depends on the skin site of sensitization, with differences driven by divergent activation states of cDC2s from different dermal tissues. Enhanced costimulatory molecule expression by cDC2s in Th2-inducing LNs promotes prolonged T cell activation, macro-clustering, and cytokine sensing. These findings show that enhanced costimulation and integrin-driven prolonged T-DC crosstalk promote T cell macro-clustering and generate LN microenvironments that drive Th2 response formation in vivo. The study also highlights the role of upstream barrier tissues in shaping T cell responses and raises questions about the mechanisms leading to divergent responses across skin sites. Th2 macro-clustering and differentiation are site-specific, with differences observed between ear and footpad immunization. These differences are mediated by non-equivalent expression of costimulatory molecules by migratory cDCs. The study also shows that prolonged costimulatory molecule availability from cDC2s promotes T cell macro-clustering and Th2 differentiation. The integrin LFA-1 is involved in prolonged T cell-DC interactions, and its blockade reduces Th2 differentiation and macro-clustering. These findings suggest that site-specific differences in cDC2 activation and costimulatory molecule expression drive Th2 responses in vivo.Th2 responses protect against pathogens but can also cause allergic inflammation. This study investigates how Th2 differentiation occurs in lymph nodes (LNs) after cutaneous allergen exposure. Using quantitative imaging, the researchers found that early Th2 cells form "macro-clusters" with migratory type-2 dendritic cells (cDC2s), creating specialized Th2-promoting microenvironments. These clusters are integrin-mediated and enhance cytokine exchange, promoting Th2 differentiation. This behavior contrasts with Th1 responses. The formation of Th2 macro-clusters depends on the skin site of sensitization, with differences driven by divergent activation states of cDC2s from different dermal tissues. Enhanced costimulatory molecule expression by cDC2s in Th2-inducing LNs promotes prolonged T cell activation, macro-clustering, and cytokine sensing. These findings show that enhanced costimulation and integrin-driven prolonged T-DC crosstalk promote T cell macro-clustering and generate LN microenvironments that drive Th2 response formation in vivo. The study also highlights the role of upstream barrier tissues in shaping T cell responses and raises questions about the mechanisms leading to divergent responses across skin sites. Th2 macro-clustering and differentiation are site-specific, with differences observed between ear and footpad immunization. These differences are mediated by non-equivalent expression of costimulatory molecules by migratory cDCs. The study also shows that prolonged costimulatory molecule availability from cDC2s promotes T cell macro-clustering and Th2 differentiation. The integrin LFA-1 is involved in prolonged T cell-DC interactions, and its blockade reduces Th2 differentiation and macro-clustering. These findings suggest that site-specific differences in cDC2 activation and costimulatory molecule expression drive Th2 responses in vivo.