T-cell priming by dendritic cells in lymph nodes occurs in three distinct phases. The study uses two-photon microscopy to observe T-cell and dendritic cell interactions in lymph nodes. T cells first undergo multiple short encounters with DCs, decreasing motility and upregulating activation markers. Then, T cells form stable contacts with DCs, secreting cytokines like IL-2 and IFN-γ. Finally, T cells resume rapid migration and short DC contacts. This three-phase process is crucial for T-cell activation. The study also shows that T-cell priming by DCs is influenced by the presence of antigen and the duration of T-cell dwell time in lymph nodes. The findings highlight the importance of DC-T cell interactions in the immune response and provide insights into the molecular mechanisms underlying T-cell activation. The research was supported by grants from the National Institutes of Health, the National Science Foundation, and the Dutch Cancer Society. The authors declare no competing financial interests. Correspondence should be addressed to G.Q.D. (george.daley@childrens.harvard.edu).T-cell priming by dendritic cells in lymph nodes occurs in three distinct phases. The study uses two-photon microscopy to observe T-cell and dendritic cell interactions in lymph nodes. T cells first undergo multiple short encounters with DCs, decreasing motility and upregulating activation markers. Then, T cells form stable contacts with DCs, secreting cytokines like IL-2 and IFN-γ. Finally, T cells resume rapid migration and short DC contacts. This three-phase process is crucial for T-cell activation. The study also shows that T-cell priming by DCs is influenced by the presence of antigen and the duration of T-cell dwell time in lymph nodes. The findings highlight the importance of DC-T cell interactions in the immune response and provide insights into the molecular mechanisms underlying T-cell activation. The research was supported by grants from the National Institutes of Health, the National Science Foundation, and the Dutch Cancer Society. The authors declare no competing financial interests. Correspondence should be addressed to G.Q.D. (george.daley@childrens.harvard.edu).