Limits...
Small intestinal intraepithelial TCRγδ+ T lymphocytes are present in the premature intestine but selectively reduced in surgical necrotizing enterocolitis.

Weitkamp JH, Rosen MJ, Zhao Z, Koyama T, Geem D, Denning TL, Rock MT, Moore DJ, Halpern MD, Matta P, Denning PW - PLoS ONE (2014)

Bottom Line: In 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).

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Vanderbilt University School of Medicine and Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, Tennessee, United States of America.

ABSTRACT

Background: Gastrointestinal 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.

Objective: We 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.

Results: In 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.

Conclusion: Complimentary 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.

Show MeSH

Related in: MedlinePlus

Developmental regulation of γδ IEL subsets in humans.Logarithmic transformed percentages of γδ IEL were plotted against gestational age (GA), postmenstrual age (PMA  =  gestational age plus chronological age) and age. Using Pearson's correlation coefficient we did not detect any association of γδ IEL proportions with GA, PMA or age in either NEC or non-NEC control patients.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4048281&req=5

pone-0099042-g002: Developmental regulation of γδ IEL subsets in humans.Logarithmic transformed percentages of γδ IEL were plotted against gestational age (GA), postmenstrual age (PMA  =  gestational age plus chronological age) and age. Using Pearson's correlation coefficient we did not detect any association of γδ IEL proportions with GA, PMA or age in either NEC or non-NEC control patients.

Mentions: Since NEC predominantly affects preterm infants, we examined whether γδ IEL are developmentally regulated in the preterm intestine. We examined the relationship between γδ IEL proportions and gestational age, postmenstrual age, and age. We did not observe a clear association between γδ IEL proportions and postmenstrual age or postnatal age, suggesting that even the most premature infants contain significant fractions of natural γδ IELs at birth [33] (Figure 2). Interestingly, the relationship between γδ IEL proportions and gestational age in non-NEC surgical control samples followed a U-shaped distribution as determined by nonlinear regression. This model accounted for 37% of the variance of the data (R2 = 0.37). The observed data did not deviate significantly from the model curve as determined by the runs test (p = 0.31). This distribution suggests a possible window of vulnerability for NEC across gestation (Figure 3).


Small intestinal intraepithelial TCRγδ+ T lymphocytes are present in the premature intestine but selectively reduced in surgical necrotizing enterocolitis.

Weitkamp JH, Rosen MJ, Zhao Z, Koyama T, Geem D, Denning TL, Rock MT, Moore DJ, Halpern MD, Matta P, Denning PW - PLoS ONE (2014)

Developmental regulation of γδ IEL subsets in humans.Logarithmic transformed percentages of γδ IEL were plotted against gestational age (GA), postmenstrual age (PMA  =  gestational age plus chronological age) and age. Using Pearson's correlation coefficient we did not detect any association of γδ IEL proportions with GA, PMA or age in either NEC or non-NEC control patients.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4048281&req=5

pone-0099042-g002: Developmental regulation of γδ IEL subsets in humans.Logarithmic transformed percentages of γδ IEL were plotted against gestational age (GA), postmenstrual age (PMA  =  gestational age plus chronological age) and age. Using Pearson's correlation coefficient we did not detect any association of γδ IEL proportions with GA, PMA or age in either NEC or non-NEC control patients.
Mentions: Since NEC predominantly affects preterm infants, we examined whether γδ IEL are developmentally regulated in the preterm intestine. We examined the relationship between γδ IEL proportions and gestational age, postmenstrual age, and age. We did not observe a clear association between γδ IEL proportions and postmenstrual age or postnatal age, suggesting that even the most premature infants contain significant fractions of natural γδ IELs at birth [33] (Figure 2). Interestingly, the relationship between γδ IEL proportions and gestational age in non-NEC surgical control samples followed a U-shaped distribution as determined by nonlinear regression. This model accounted for 37% of the variance of the data (R2 = 0.37). The observed data did not deviate significantly from the model curve as determined by the runs test (p = 0.31). This distribution suggests a possible window of vulnerability for NEC across gestation (Figure 3).

Bottom Line: In 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).

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Vanderbilt University School of Medicine and Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, Tennessee, United States of America.

ABSTRACT

Background: Gastrointestinal 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.

Objective: We 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.

Results: In 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.

Conclusion: Complimentary 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.

Show MeSH
Related in: MedlinePlus