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Microanatomical dissection of human intestinal T-cell immunity reveals site-specific changes in gut-associated lymphoid tissues over life

Mucosal Immunology (2018) | Download Citation

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Abstract

Defining adaptive immunity with the complex structures of the human gastrointestinal (GI) tract over life is essential for understanding immune responses to ingested antigens, commensal and pathogenic microorganisms, and dysfunctions in disease. We present here an analysis of lymphocyte localization and T cell subset composition across the human GI tract including mucosal sites (jejunum, ileum, colon), gut-associated lymphoid tissues (isolated lymphoid follicles (ILFs), Peyer’s patches (PPs), appendix), and mesenteric lymph nodes (MLNs) from a total of 68 donors spanning eight decades of life. In pediatric donors, ILFs and PP containing naïve T cells and regulatory T cells (Tregs) are prevalent in the jejunum and ileum, respectively; these decline in frequency with age, contrasting stable frequencies of ILFs and T cell subsets in the colon. In the mucosa, tissue resident memory T cells develop during childhood, and persist in high frequencies into advanced ages, while T cell composition changes with age in GALT and MLN. These spatial and temporal features of human intestinal T cell immunity define signatures that can be used to train predictive machine learning algorithms. Our findings demonstrate an anatomic basis for age-associated alterations in immune responses, and establish a quantitative baseline for intestinal immunity to define disease pathologies.

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Acknowledgements

This work was supported by NIH grants AI06697 and AI100119 awarded to D.L.F. P.D. was supported by a CRI-Irvington postdoctoral fellowship. Research reported here was performed in the CCTI Flow Cytometry Core, supported in part by the Office of the Director, National Institutes of Health under award S10RR027050. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We wish to gratefully acknowledge the generosity of the donor families and the exceptional efforts of LiveOnNY transplant coordinators and staff for making this study possible, and Dr Keita Okubo for help with donor tissue acquisition.

Author information

Author notes

    • Tomer Granot

    Present address: Compugen, San Francisco, CA, USA

Affiliations

  1. Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY, 10032, USA

    • Takashi Senda
    • , Pranay Dogra
    • , Tomer Granot
    • , Kazuhiro Furuhashi
    • , Mark E. Snyder
    • , Dustin J. Carpenter
    • , Peter A. Szabo
    • , Puspa Thapa
    • , Michelle Miron
    •  & Donna L. Farber
  2. Department of Surgery, Columbia University Medical Center, New York, NY, 10032, USA

    • Takashi Senda
    • , Dustin J. Carpenter
    •  & Donna L. Farber
  3. Department of Medicine, Columbia University Medical Center, New York, NY, 10032, USA

    • Pranay Dogra
    • , Tomer Granot
    • , Mark E. Snyder
    • , Peter A. Szabo
    •  & Puspa Thapa
  4. Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY, 10032, USA

    • Michelle Miron
    •  & Donna L. Farber

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Contributions

T.S. designed the experiments, obtained donor tissues, processed tissues, performed flow cytometry and tissue imaging experiments, collected the data, and wrote the paper; P.D. performed the statistical analysis, visualized the data, created machine learning models, and helped write the paper; D.J.C. obtained donor tissues; T.G, P.D., P.A.S., P.T., and M.M. processed tissues; K.F. assisted with tissue imaging experiments; D.L.F planned experiments, coordinated tissue acquisition and data acquisition/analysis, analyzed data, and wrote the paper.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Donna L. Farber.

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DOI

https://doi.org/10.1038/s41385-018-0110-8