The gut microbiota directs vitamin A flux to regulate intestinal T cell development

Keywords ● Microbiome ● Retinoids ● CD4+T cells

Main Findings

The gut microbiome is intricately linked with immune cell maturation and function. In fact, antigen-presenting myeloid cells in the lamina propria can capture live microbes/microbial antigens and migrate to the mesenteric lymph nodes (mLNs) where they prime naïve CD4+ T cells. However, this process is disrupted in vitamin A-deficient mice. Bang et al (Science 2021) previously found that gut microbes drive the production of serum amyloid A (SAAs) proteins in intestinal epithelial cells that bind and facilitate vitamin A-derived retinoid transfer to intestinal myeloid cells.

Now, Srinivasan et al (not peer reviewed) have set out to mechanistically dissect the interplay between gut microbes and SAAs in regulating retinoid transfer, myeloid migration to the mLN, and subsequent CD4+ T cellmaturation and gut homing. Using a series of orthogonal assays, the authors spatiotemporally mapped retinoid flux from intestinal epithelial cells to CD11c+myeloid cells and then to developing CD4⁺ T cells in the mLN—a process that takes roughly 3 days. Retinoid flux across cell types was accompanied by retinoic acid receptor (RAR) signaling and RA-dependent transcriptional programs. Further, retinoid transfer along this epithelial–myeloid–T cell axis requires both gut microbiota and SAAs. Interestingly, the authors observe that the delivery of retinoids from CD11c+ myeloid cells to CD4⁺ T cells in the mLN is dependent on an intact gut microbiome and propose that microbial antigen presentation and recognition facilitate this final transfer. They also identify segmented filamentous bacteria (SFB) as potent enhancers of this pathway, though unlikely the only bacterial contributors.

This manuscript also aims to delineate the mechanism by which the presence of gut microbes trigger SAA production in intestinal epithelial cells. Mechanistically, the authors find that microbe-associated molecular patterns (MAMPs) engage Toll-like receptors (TLRs) on CD11c+ myeloid cells, which drive interleukin-23 (IL-23) production through the MYD88 adaptor. IL-23 subsequently stimulates IL-22 secretion from innate lymphoid cells (ILC3) which, ultimately, drive Saa gene transcription in intestinal epithelial cells though the STAT3 pathway.

Lastly, the authors report that retinoid flux is most active during early postnatal development, a critical window when the gut microbiota expands and the adaptive immune system matures.

Overall, this study presents a comprehensive model to describe the distinct roles of both gut microbes and SAA proteins in regulating vitamin A-derived retinoid flux from the gut to the mLN. These findings redefine the relationship between the microbiota, nutrition, and immune development—suggesting that microbial presence not only provides antigenic cues but also orchestrates micronutrient delivery and aid in intestinal CD4⁺ T cell maturation and homing.

Limitations

• The final stage of retinoid transfer from CD11c+myeloid cells to CD4+ T cells transfer in the mLN is interesting but incomplete. Additional studies should be performed to measure microbial antigen load in the mLN and determine whether microbial antigen presentation alone is sufficient for retinoid delivery.

• The present study focuses broadly on CD11c+ myeloid cells—a heterogenous population that contains macrophages and DCs.

• The study does not explicitly determine how CCR7 expression on CD11c+ myeloid cells is regulated by retinoids.

• All the mechanistic data in the paper is derived from mouse models exclusively.

Significance/Novelty

This study demonstrates a novel mechanism by which the gut microbiota directly controls vitamin A flux from the intestine to the mLN—contributing to improved CD4+ T cell maturation and gut homing. It distinguishes two phases of retinoid transfer: an initial phase driven by SAAs followed by a microbial-dependent phase. These findings could significantly contribute to our understanding of early postnatal immune system development and even guide dietary intervention opportunities.

Recommendations

• Additional studies should be performed to directly address retinoid tranfer from CD11c+ myeloid cells to CD4+ T cells in the mLN. It would be important to measure microbial antigen load in the mLN and determine whether microbial antigen presentation alone is sufficient for retinoid delivery.

• CD4+T cell maturation is currently only evaluated by gene expression. Functional studies would significantly improve the claim that retinoid transfer is required for optimal CD4+ T cell development.

• Delineating specific bacteria that activate SAA expression and mLN translocation would provide translational potential.

• Single-cell RNA-seq or flow cytometry with additional immunophenotyping markers for myeloid cell populations could identify which subsets are responsible for retinoid uptake versus antigen presentation.

Preprint rating

· Scientific quality: *****

· Novelty:****

· Significance:****

Credit

Reviewed by Shelley Herbrich as part of a cross-institutional journal club between the Icahn School of Medicine at Mount Sinai, the University of Oxford, the Karolinska Institute, the University of Toronto and MD Anderson Cancer Center.

The author declares no conflict of interests in relation to their involvement in the review.