Postdoctoral Research Fellow Brigham and Women’s Hospital, Harvard Medical School, United States
Disclosure(s):
Marilia Garcia de Oliveira: No financial relationships to disclose
Introduction/Rationale: The intestinal epithelium is a specialized barrier that balances tolerance and defense against luminal antigens and microbes. Its maturation during early life is shaped by intraepithelial lymphocytes (IELs), the microbiota, and maternal factors. Natural CD8αα⁺ αβ and Vγ7⁺ γδ IELs are critical for epithelial homeostasis, repair, and microbial regulation, yet the mechanisms controlling their postnatal maintenance remain poorly understood.
Methods: Jackson (Jax) and Taconic (Tac) mice were evaluated by flow cytometry after cross-foster, co-house, and adoptive transfer experiments. Bulk RNA sequencing, and milk proteomic analysis were also performed.
Results: Tac mice showed fewer natural CD8αα⁺ and Vγ7⁺ γδ IELs throughout the small intestine (SI), while colonic frequencies remained comparable to Jax mice, indicating a compartmentalized defect. CD8αα⁺ IEL loss was microbiota-dependent, as co-housing with Jax mice restored their abundance, whereas Vγ7⁺ IEL loss was microbiota-independent and emerged at weaning despite normal thymic output. Cross-fostering Tac pups onto Jax dams fully rescued Vγ7⁺ IELs, implicating milk-derived factors. Proteomic profiling of Tac versus Jax milk revealed broad protein reductions, notably in IGF transport and uptake pathways, with decreased IGF-1 and osteopontin. Adoptive transfers showed a tissue-intrinsic defect, as Tac IELs engrafted in Jax RAG⁻/⁻ hosts but not vice versa. SI epithelial transcriptomics revealed downregulation of c-Myc targets after day 28, coinciding with Vγ7⁺ IEL loss and defective epithelial maturation.
Conclusion: Together, these findings reveal that postnatal maintenance of natural IELs depends on distinct environmental cues: while CD8αα⁺ IELs are shaped by the microbiota, Vγ7⁺ γδ IELs require maternal milk–derived factors that support epithelial maturation and c-Myc–dependent pathways. This identifies a critical early-life window in which deficient milk signals can impair intestinal immune–epithelial development and long-term mucosal homeostasis.
