Biological rhythms in the regulatory/tolerogenic functions of the immune activity in the gut

BARRIOS B., MACCIÓ-MARETTO L., NOVOTNY NUÑEZ I., CORREA S

Mar del Plata

Congreso; Reunión Anual Conjunta SAIC-SAI-SAFE; 2016

SAIC-SAI-SAFE

In the gut, the circadian clock orchestrates temporal organization of many aspects of physiology even immunity. As intestinal environment modulates the phenotype and function of immune cells, we wonder if over a 24h period there were variations in the activation or function of cells that could affect tolerance. We evaluated activation status of CD4+ and CD8+ lymphocytes and numbers of Foxp3+ regulatory T cells (Foxp3+ Treg) in mesenteric lymph nodes (MLN) from undisturbed C57BL/6 mice at 6, 12, 18 and 24h CT. We found that both CD4+ and CD8+ T cells bearing the markers CD62L+CD69+ oscillated in 24h period time with maximum at 6/18h and minimum at 12h CT (p<0.05);similar observations were found with CD4+CD62L+CD69- cells. We also found a significant increment in the absolute number of Foxp3+ Treg cells at 18h with minimum at 6h (p<0.05) and an overall increase in the frequency of this subpopulation in the light phase of the cycle (12 and 18 h). Since intestinal environment also modulates the activity of dendritic cells (DC), we examined the ability of DC isolated from afferent lymphatics at 6, 12, 18 and 24h CT in inducing Foxp3+ Tregs and the expression of gut homing molecules, α4β7 integrin and CCL25 receptor chemokine, CCR9. When co-cultured with MLN CD4+Foxp3- cells sorted from GFP-Foxp3 mice, DC isolated at 18h showed higher ability to induce in CD4+ cells Foxp3 as well as α4β7 and CCR9 expression. These results show that the activation of T cells fluctuate along the dark and ligh cycle phases. These variations can be explained by changes in both the potential of tolerogenic DC and the frequency of Foxp3+ Treg cells. Together these circadian oscillations could contribute to greater plasticity in the balance immunity / tolerance in intestinal mucosa.