Time-dependent imprinting of gut homing receptors on lymphocytes by migratory antigen presenting cells

Abstract

Circadian rhythms synchronize many physiological and immune processes, but their role in coordinating intestinal lymphocyte trafficking remains unclear. Here, we investigated the temporal regulation of gut homing receptors, α4β7 integrin and CCR9 chemokine receptor, on lymphocyte subsets and the involvement of migratory antigen presenting cells 5r4 in this process. Using wild-type and Period 2 (Per2) knockout mice, we analyzed receptor expression on CD4+, CD8+, and B lymphocytes from mesenteric lymph nodes (MLNs) at four Zeitgeber times (ZT5, ZT11, ZT17, ZT23). We observed circadian oscillations in homing receptor expression, with peaks at ZT5 in T cells and at ZT11–17 in B cells. Disruption of light-dark cycles increased α4β7 and CCR9 expression, particularly in B lymphocytes, highlighting their sensitivity to circadian misalignment. Migratory APCs isolated from afferent lymphatics showed time-dependent variation in their capacity to induce these receptors on naïve CD4+Foxp3- T cells in co-culture, correlating with elevated β-catenin and transforming growth factor-beta (TGF-β) levels. In Per2 knockout mice, this circadian pattern was impaired. Multivariate analysis revealed three distinct temporal phenotypes of homing receptor expression. These findings indicate that circadian rhythms modulate lymphocyte gut homing via migratory APC function, and disruptions in circadian cues could contribute to altered mucosal immune responses in intestinal diseases.