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

Abstract

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 pMHC DCs and to find rare pMHC 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.

Stable contacts of naïve CD4 T cells with migratory dendritic cells are ICAM-1-dependent but dispensable for proliferation in vivo

“…Naïve T cells make fate decisions within hours after antigen exposure, resulting in activation, proliferation and either long-term memory or abortive effector responses, which correlate with T cell-DCs interaction kinetics [1][2][3][4]. The LFA-1 integrin on T cells and its two main ligands ICAM-1 and ICAM-2 expressed by DCs as well as by other antigen presenting cells (APCs) were suggested to modulate the strength, the kinetics, and hence the outcome of these interactions [5,6].…”

Initial Viral Inoculum Determines Kinapse-and Synapse-Like T Cell Motility in Reactive Lymph Nodes

“…To dissect the influence of pMHC levels on T cell motility patterns, ex vivo activated DCs were pulsed with defined levels of cognate peptide prior to injection into recipient mice, while T cell dwell times were controlled by a short homing window. This approach identified a multistep model of T cell activation, according to which T cells dynamically respond to pMHC levels (4–8). When intermediate levels of cognate pMHC are presented on activated DCs, motile T cells scan DCs for a period of a few h (phase 1; 0–8 h post LN entry).…”

“…After ~20 h, activated T cells detach and resume motility before starting cell division (phase 3) (14, 15). Subsequent studies have refined the 3-phase concept by showing that pulsing DCs with high amounts of peptide induces immediate arrest, i.e., instantaneous phase 2 induction (5, 7, 8). In contrast, T cells may skip phase 2, i.e., stable interactions, with DCs at very low antigen dose, yet still expand during the effector phase (6).…”

Salivary gland macrophages assist tissue-resident CD8+T cell immune surveillance

“…The given binomial proportion 95% confidence intervals are Wilson Score intervals. We generated 100 synthetic tracks of 12 h duration for each condition using a sampling strategy, which was designed to preserve the correlation between velocity and turning angle and the autocorrelation of velocity and turning angle ( 10 ). We then took the first timestep further than 40 µm away from the origin of each track as simulated dwelling time in an acinus of 80 µm diameter.…”

“…Naïve CD8 + T cells (T N ) continuously traffic through lymphoid tissue such as peripheral lymph nodes (PLN) and spleen, where they screen antigen presenting dendritic cells (DCs) for the presence of cognate peptide-MHC (pMHC) complexes. Intravital two-photon microscopy (2PM) of peripheral lymph nodes (PLN) uncovered a high amoeboid-like T N motility of 12-15 µm/min ( 1–4 ), facilitating their search for rare cognate pMHC-presenting DCs interspersed on a 3D stromal scaffold of fibroblastic reticular cells (FRC) ( 5–10 ). Intranodal motility is mediated by the CCR7 ligands CCL19 and CCL21 that drive F-actin polymerization at the leading edge in a Gαi-dependent manner to generate a retrograde cortical actin flow.…”