Abstract
BackgroundGastrointestinal barrier immaturity predisposes preterm infants to necrotizing enterocolitis (NEC). Intraepithelial lymphocytes (IEL) bearing the unconventional T cell receptor (TCR) γδ (γδ IEL) maintain intestinal integrity and prevent bacterial translocation in part through production of interleukin (IL) 17.ObjectiveWe sought to study the development of γδ IEL in the ileum of human infants and examine their role in NEC pathogenesis. We defined the ontogeny of γδ IEL proportions in murine and human intestine and subjected tcrδ−/− mice to experimental gut injury. In addition, we used polychromatic flow cytometry to calculate percentages of viable IEL (defined as CD3+ CD8+ CD103+ lymphocytes) and the fraction of γδ IEL in surgically resected tissue from infants with NEC and gestational age matched non-NEC surgical controls.ResultsIn human preterm infants, the proportion of IEL was reduced by 66% in 11 NEC ileum resections compared to 30 non-NEC controls (p<0.001). While γδ IEL dominated over conventional αβ IEL early in gestation in mice and in humans, γδ IEL were preferential decreased in the ileum of surgical NEC patients compared to non-NEC controls (50% reduction, p<0.05). Loss of IEL in human NEC was associated with downregulation of the Th17 transcription factor retinoic acid-related orphan nuclear hormone receptor C (RORC, p<0.001). TCRδ-deficient mice showed increased severity of experimental gut injury (p<0.05) with higher TNFα expression but downregulation of IL17A.ConclusionComplimentary mouse and human data suggest a role of γδ IEL in IL17 production and intestinal barrier production early in life. Specific loss of the γδ IEL fraction may contribute to NEC pathogenesis. Nutritional or pharmacological interventions to support γδ IEL maintenance in the developing small intestine could serve as novel strategies for NEC prevention.
Highlights
A critical, yet understudied, area in neonatology is the development of intestinal immune regulation in preterm infants, who are prone to exaggerated inflammatory host responses to bacterial antigens [1]
While cd Intraepithelial lymphocytes (IEL) dominated over conventional ab IEL early in gestation in mice and in humans, cd IEL were preferential decreased in the ileum of surgical necrotizing enterocolitis (NEC) patients compared to non-NEC controls (50% reduction, p, 0.05)
Specific loss of the cd IEL fraction may contribute to NEC pathogenesis
Summary
A critical, yet understudied, area in neonatology is the development of intestinal immune regulation in preterm infants, who are prone to exaggerated inflammatory host responses to bacterial antigens [1]. One example is necrotizing enterocolitis (NEC), a common, potentially lethal disease, primarily affecting preterm infants. Gestational age (weeks) Age (days) Postmenstrual age (weeks) Female P values. Continuous data are summarized with median (quartiles), and categorical data with percent (frequency). P values are computed with Wilcoxon rank sum test (continuous) and Fisher’s exact test (categorical). Gastrointestinal barrier immaturity predisposes preterm infants to necrotizing enterocolitis (NEC). Intraepithelial lymphocytes (IEL) bearing the unconventional T cell receptor (TCR) cd (cd IEL) maintain intestinal integrity and prevent bacterial translocation in part through production of interleukin (IL) 17
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