Intestinal CD103+ dendritic cells induced by short-term fasting are essential for the protection against Listeria monocytogenes infection

Abstract

Despite the fact that gastrointestinal tract is the largest organ producing and consuming a great amount of energy and the first organ to be directly affected after the fasting, very little is known about how fasting influences intestinal immune cells. Innate immune cells in gastrointestinal tract play a critical role as an initial sensor of antigens and inducer of proper immune response. In the current study, I focused on the changes of intestinal innate cells, especially CD103+ dendritic cells (DCs), in mice upon 24 hr short-term fasting and how the fasting influences the protection against intragastric Listeria monocytogenes (L. monocytogenes) infection. The results showed that the mice with short-term fasting increased the number of CD103+CD11b- DCs in both small intestinal lamina propria (SI LP) and mesenteric lymph nodes (mLN) after either fasting or fasting followed by infection. Induction of SI LP CD103+CD11b- DCs during short-term fasting was caused by active proliferation, but this phenomenon was confined only in SI LP. Furthermore, the expression of CCR7, PD-L1 and CD205 was up-regulated on CD103+CD11b- DCs in mice which had been short-term fasting and infected with L. monocytogenes. Surprisingly, short-term fasting increased the survival rate compared to control (ad libitum) mice when infected with L. monocytogenes. At early time points post infection (pi

3, 9 and 24 hr), there was no significant difference in bacterial clearance

strikingly, at 48 hr pi, however, bacterial clearance was significantly increased in spleen, liver and mLN from starved mice compared to control mice, as measured by colony forming units (CFU) of L. monocytogenes. Mechanistically, at the early time points pi, the increase of CD103+CD11b- DCs after fasting induced significantly high Foxp3+ Tregs in mLN, which was in line with increased mRNA level of TGF-β2 and aldehyde dehydrogenase A2 (aldh1a2). Curiously, at 3 days pi, the composition of CD11chi DCs was entirely altered toward the expansion of CD103- DCs, with induction of IFN-γ+ NK cells and CD4+ and CD8+ T cells in mLN. The present study suggests that short-term fasting might induce the tolerogenic condition in the small intestine through increased CD103+CD11b- DCs. Accordingly, at day 1 pi, Foxp3+ Tregs were significantly increased. However, at day 2 pi, the L. monocytogenes bacterial burden was significantly reduced and at the same time, CD103- DCs and IFN-γ+ cells were prominently increased in mLN. Collectively, the results showed that the constitution of intestinal CD11chi DCs would be a key player for the maintenance of gut homeostasis and/or induction of immunity.