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

Ackerknecht, Markus; Gollmer, Kathrin; Germann, Philipp; Ficht, Xenia Maria; Abe, Jun; Fukui, Yoshinori; Swoger, Jim; Ripoll, Jorge; Sharpe, James; Stein, Jens Volker (2017). Antigen Availability and DOCK2-Driven Motility Govern CD4\mathplusT Cell Interactions with Dendritic Cells In Vivo. Journal of immunology, 199(2), pp. 520-530. American Association of Immunologists 10.4049/jimmunol.1601148

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Parenchymal migration of naive CD4+ T cells in lymph nodes (LNs) is mediated by the Rac activator DOCK2 and PI3Kγ 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 PI3Kγ 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 pMHClow DCs and to find rare pMHChigh 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.

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