Quantification of lymph node transit times reveals differences in antigen surveillance strategies of naïve CD4⁺ and CD8⁺ T cells

Naïve T cells continually recirculate between blood and secondary lymphoid organs, scanning dendritic cells (DC) for foreign antigen. Despite its importance for understanding how adaptive immune responses are efficiently initiated from rare precursors, a detailed quantitative analysis of this fundamental process has not been reported. Here we measure lymph node (LN) entry, transit, and exit rates for naïve CD4 ⁺ and CD8 ⁺ T cells, then use intravital imaging and mathematical modeling to relate cell–cell interaction dynamics to population behavior. Our studies reveal marked differences between CD4 ⁺ vs. CD8 ⁺ T cells. CD4 ⁺ T cells recirculate more rapidly, homing to LNs more efficiently, traversing LNs twice as quickly, and spending ∼1/3 of their transit time interacting with MHCII on DC. In contrast, adoptively transferred CD8 ⁺ T cells enter and leave the LN more slowly, with a transit time unaffected by the absence of MHCI molecules on host cells. Together, these data reveal an unexpectedly asymmetric role for MHC interactions in controlling CD4 ⁺ vs. CD8 ⁺ T lymphocyte recirculation, as well as distinct contributions of T cell receptor (TCR)-independent factors to the LN transit time, exposing the divergent surveillance strategies used by the two lymphocyte populations in scanning for foreign antigen.