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Abstract

Infants are susceptible to mucocutaneous candidiasis, which manifests via oral thrush and diaper rashes. Th17 cells are responsible for limiting mucosal invasion by commensal Candida spp. Dysregulated Th17 cells are also involved in necrotizing enterocolitis (NEC) pathogenesis, a surgical complication of the gut affecting about 5% of pre-term neonates. It was previously shown that neonatal peripheral blood naïve T cells produce low levels of IL-17, which might be protective against NEC while increasing susceptibility to mucocutaneous candidiasis. However, neonatal naïve CD4 T cells inherently produced high levels of IL-22 upon stimulation by Th17 cells. We sought the molecular mechanism underpinning the developmental lack of IL-17 responses in circulating blood T cells from neonates. A genome-wide transcriptome analysis comparing neonatal and adult naïve CD4 T cells revealed major developmental differences in the expression profile of genes associated with SMAD and STAT3 signaling. Functional assays confirmed that the requirement for TGF-β in human Th17 cell differentiation increased with age. Moreover, expression of STAT3 was relatively lower in neonatal naïve CD4 T cells; accordingly, overexpression of the STAT3 gene in naïve CD4 T cells restored IL-17 production in neonatal Th17 cells. Moreover, I generated infant (<6 months old)- and pediatric (6-14 years old)-derived enteroids and co-cultured them with recombinant human IL-22 and supernatant from Th17 cells, to investigate the effect of neonatal Th17 cells, a frequent type of T cell in the intestine, on the function of intestinal epithelial cells. I hypothesized that infants’ gut epithelium is developmentally different when compared to older children and that neonatal Th17 cell-produced IL-22 plays an important protective role in the gut. Indeed, I show that IL-22-treated enteroids upregulate antimicrobial genes such as Reg3𝛂⧸𝜸. Infant-derived enteroids also showed exaggerated proliferation and mucus production compared to pediatric enteroids, after exposure to Th17 cell supernatants. The infant gut epithelium demonstrated increased proliferation and epithelial cells differentiation as compared to pediatric enteroids, as evidenced by higher expression of Ki67 and MUC2, respectively. These data suggest developmental cross-talk between Th17 cells and gut epithelium, as a means to maintain a healthy gut in the context of an undeveloped immune system.