Small Intestinal Intraepithelial TCRγδ+ T Lymphocytes Are Present in the Premature Intestine but Selectively Reduced in Surgical Necrotizing Enterocolitis

• Type of Material: Article
• Authors: Jörn-Hendrik Weitkamp, Vanderbilt University School of Medicine; Michael J. Rosen, affiliationCincinnati Children's Hospital Medical Center; Zhiguo Zhao, Vanderbilt University School of Medicine; Tatsuki Koyama, Vanderbilt University School of Medicine; Duke Geem, Georgia State University; Timothy L. Denning, Georgia State University; Michael T. Rock, Vanderbilt University School of Medicine; Daniel J. Moore, Vanderbilt University School of Medicine; Melissa D. Halpern, University of Arizona; Pranathi Matta, Vanderbilt University School of Medicine; Patricia Denning, Emory University
• Language: English
• Date: 2014
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2014 Weitkamp et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0099042
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 9
• Issue: 6
• Start Page: e99042
• End Page: e99042
• Grant/Funding Information: Support for flow cytometry experiments and biostatistics was provided through the Vanderbilt University Medical Center's Digestive Disease Research Center sponsored by NIH grant P30DK058404 and Emory University's Digestive Diseases Research Development Core sponsored by NIH grant DK 063399.; This project was supported by award number K08HD061607 (to JHW) and R01HD05922 (to PWD) from the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD).; This work was also supported by the Vanderbilt Physician Scientist Development Program Award (to JHW), NIH Award K23DK094832 (to MJR), the Vanderbilt CTSA grant UL1 RR024975-01 from NCRR/NIH (now NCATS/NIH grant 2 UL1 TR000445-06), 5K08DK090146-03 (to DJM) and by a Vanderbilt DRTC Pilot Grant P30DK20593 (to DJM).
• Research Categories: Health Sciences, General

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.