Peripheral Lymphoid Volume Expansion and Maintenance Are Controlled by Gut Microbiota via RALDH+ Dendritic Cells

Abstract

Summary Lymphocyte homing to draining lymph nodes is critical for the initiation of immune responses. Secondary lymphoid organs of germ-free mice are underdeveloped. How gut commensal microbes remotely regulate cellularity and volume of secondary lymphoid organs remains unknown. We report here that driven by commensal fungi, a wave of CD45+CD103+RALDH+ cells migrated to the peripheral lymph nodes after birth. The arrival of these cells introduced a high amounts of retinoic acid, mediated the neonatal to adult addressin switch on endothelial cells, and directed the homing of lymphocytes to both gut-associated lymphoid tissues and peripheral lymph nodes. In adult mice, a small number of these RALDH+ cells may serve to maintain the volume of secondary lymphoid organs. Homing deficiency of these cells was associated with lymph node attrition in Vitamin A-deficient mice, suggesting a perpetual dependence on retinoic acid signaling for structural and functional maintenance of peripheral immune organs.

Commensal Fungi in Health and Disease

“…A recent study in mice suggests that fungi in early life may play an important role in the maturation of secondary lymphoid organs by promoting intestinal trafficking of dendritic cells expressing the retinoic acid-synthesizing enzyme RALDH to peripheral lymph nodes where, via a mechanism involving production of retinoic acid, they promote homing of lymphocytes to both gut-associated lymphoid tissues and peripheral lymph nodes (Zhang et al, 2016). Whether a similar mechanism is at work in developing humans is not yet known.…”

The mammalian mycobiome: A complex system in a dynamic relationship with the host

“…This defect in the formation of lymphoid structures impairs the ability of the host to mount protective adaptive immune responses to infections (van de Pavert et al, ). Interestingly, Shi and coworkers identified symbiont fungi but not bacteria as primary drivers of the maturation of SLOs in mice (Z. Zhang et al, ). Development of SLOs requires a wave of migration of dendritic cells (DCs) expressing the retinol dehydrogenase enzyme, RALDH, from the intestines into peripheral lymph nodes in neonatal mice.…”

“…Interestingly, Shi and coworkers identified symbiont fungi but not bacteria as primary drivers of the maturation of SLOs in mice (Z. Zhang et al, 2016). Development of SLOs requires a wave of migration of dendritic cells (DCs) expressing the retinol dehydrogenase enzyme, RALDH, from the intestines into peripheral lymph nodes in neonatal mice.…”

Host–microbe interactions: commensal fungi in the gut

“…Further, they observed a similar reduction of RALDH + DCs in gut- and skin-draining LNs in wild-type mice treated with an anti-fungal cocktail but not in mice with an antibacterial treatment. Oral gavage with a mouse commensal fungal species, Candida tropicalis , was sufficient to enhance migration of gut RALDH + DCs, to peripheral lymph nodes and promotes development of gut lymphoid tissues [40] (Fig. 2).…”