Fig. 4: Modeling a multi-stage process for adaptive immunity by integrating cell-intrinsic rhythms.

a Dynamics of the individual rhythmic components of T cell (red) and dendritic cells (DCs, blue) migration to the lymph node (LN), as well as T cell proliferation (black) as predicted by the mathematical models (ID1-3, Supplementary Table 1) with Z-score for each dynamic being shown. The solid lines indicate the mean (for T cell homing) or the best fit (for DC homing and T cell proliferation), while colored shaded areas represent 95%-confidence intervals. T cell velocity (purple) was only measured at ZT7 and ZT19, leading to a stepwise function. The orange shaded area indicates a time window for potential optimal interactions of rhythmic components around ZT7. b Mathematical model (Supplementary Note 1) describing the migration and interaction of T cells and DC to and within the LN. T-DC interactions lead to activated T cells (orange) that proliferate in a rhythmic manner, and mediate feedback on the homing and egress dynamics of T cells. c Predicted effect of individually ablating rhythmic homing (T + DC) or proliferation (T) on LN expansion at day 6 post-injection relative to an arrhythmic scenario. Individual data points show predicted fold ratio for each skin draining LNs using the best fit, with bars and whiskers indicating the mean ± 1.96 × SEM, n = 3 mice. d Schematic depicting stages of initial immune response and clock interactions. Antigen-presenting cell (APCs) trafficking is regulated by clocks in endothelial cells (green) and APCs (blue), leading to temporal variation in APC numbers reaching the LN. This feeds into rhythms in the acute LN response to influence recruitment dynamics of effector cells (red). Downstream and independent of these rhythmic events, effector cells can maintain a rhythmic proliferation capacity, ultimately leading to temporal variation in long-term immunity. e, f Leukocyte counts 48 h post-treatment in WT and T cell-specific Bmal1^−/− (BMAL1^ΔTcell) mice in e parotid LNs, n = 3–7 mice; and f popliteal LNs, n = 4–11 mice; two-way ANOVA with Tukey’s post test. Data are plotted as mean ± standard error of mean (SEM); ns, not significant. Source data are provided as a Source data file and detailed sample sizes are available in “Methods”.