Antigen Availability and DOCK2-Driven Motility Govern CD4+ T Cell Interactions with Dendritic Cells In Vivo

Parenchymal migration of naive CD4(+) T cells in lymph nodes (LNs) is mediated by the Rac activator DOCK2 and PI3K gamma and is widely assumed to facilitate efficient screening of dendritic cells ( DCs) presenting peptide-MHCs ( pMHCs). Yet how CD4(+) T cell motility, DC density, and pMHC levels interdependently regulate such interactions has not been comprehensively examined. Using intravital imaging of reactive LNs in DC-immunized mice, we show that pMHC levels determined the occurrence and timing of stable CD4(+) T cell-DC interactions. Despite the variability in interaction parameters, ensuing CD4(+) T cell proliferation was comparable over a wide range of pMHC levels. Unexpectedly, decreased intrinsic motility of DOCK2(-/-) CD4(+) T cells did not impair encounters with DCs in dense paracortical networks and, instead, increased interaction stability, whereas PI3K gamma deficiency had no effect on interaction parameters. In contrast, intravital and whole-organ imaging showed that DOCK2-driven T cell motility was required to detach from pMHC(low) DCs and to find rare pMHC high DCs. In sum, our data uncover flexible signal integration by scanning CD4(+) T cells, suggesting a search strategy evolved to detect low-frequency DCs presenting high cognate pMHC levels.