Bone marrow by day, lymph nodes by night: Undernutrition imparts a distinct circadian rhythm to T cells in mice

Abstract

In well-nourished organisms, T cells migrate between the blood and secondary lymphoid organs, conducting surveillance for invading pathogens. T cell surveillance is under circadian control via diurnal fluctuations in corticosterone levels and undernutrition is associated with increased corticosterone. Therefore, we hypothesized that undernutrition disrupts the circadian migratory patterns of T cells. We report that compared to well-nourished controls, undernourished mice demonstrate enhanced T cell relocation to the bone marrow throughout the 24-hour period, but especially during the light phase, and diminished T cell migration to the lymph nodes only during the light phase. Undernutrition-related changes in T cell expression of key migration proteins are also mostly limited to the light phase. For example, undernourished naïve CD4+ T cells exhibited higher levels of CXCR4 and CCR7 as well as reduced levels of S1P1 compared to controls; with all changes, except for CXCR4 expression, being restricted to the light phase. These results suggest that naïve CD4+ T cells in the lymph nodes upregulate CXCR4 during the dark phase, enabling their migration to the bone marrow where they remain for the light phase. Once there, CCR7 is upregulated, presumably sending them back to the lymph node, thereby preserving immunosurveillance during the dark phase. Naïve CD4+ T cell disengagement from S1P1-related egress signals may further contribute to increased retention of cells within each compartment during the appropriate phase. Undernutrition-related increases in T cell residency of the bone marrow likely preserve T cell numbers until nutrition is restored.