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Early-life compartmentalization of human T cell differentiation and regulatory function in mucosal and lymphoid tissues

Nature Medicine volume 22, pages 7277 (2016) | Download Citation

Abstract

It is unclear how the immune response in early life becomes appropriately stimulated to provide protection while also avoiding excessive activation as a result of diverse new antigens. T cells are integral to adaptive immunity; mouse studies indicate that tissue localization of T cell subsets is important for both protective immunity1,2,3,4 and immunoregulation5,6. In humans, however, the early development and function of T cells in tissues remain unexplored. We present here an analysis of lymphoid and mucosal tissue T cells derived from pediatric organ donors in the first two years of life, as compared to adult organ donors, revealing early compartmentalization of T cell differentiation and regulation. Whereas adult tissues contain a predominance of memory T cells7,8, in pediatric blood and tissues the main subset consists of naive recent thymic emigrants, with effector memory T cells (TEM) found only in the lungs and small intestine. Additionally, regulatory T (Treg) cells comprise a high proportion (30–40%) of CD4+ T cells in pediatric tissues but are present at much lower frequencies (1–10%) in adult tissues. Pediatric tissue Treg cells suppress endogenous T cell activation, and early T cell functionality is confined to the mucosal sites that have the lowest Treg:TEM cell ratios, which suggests control in situ of immune responses in early life.

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Acknowledgements

This work was supported by the US National Institutes of Health (NIH) (grant no. AI100119; D.L.F., AI106697: D.L.F., F31AG047003; J.J.C.T., AI083022; K.L.B.) and a BD Bioscience Research Grant (J.J.C.T.). These studies were performed in the Columbia Center for Translational Immunology (CCTI) Flow Cytometry Core, funded in part through an S10 Shared Instrumentation Grant from the NIH (grant no. S10RR027050), with the excellent technical assistance of S.-H. Ho. We gratefully acknowledge the generosity of the organ donor families and the efforts of the LiveOnNY transplant coordinators and staff for making this study possible. We also wish to thank S. Mickel and B. Kumar for their assistance with tissue processing, B. Levin and N. Yudanin for their assistance with statistical analyses and K. Zens, N. Yudanin and E. Lamouse-Smith for critical reading of this manuscript.

Author information

Affiliations

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

    • Joseph J C Thome
    • , Kara L Bickham
    • , Claire Gordon
    • , Tomer Granot
    • , Adam Griesemer
    •  & Donna L Farber
  2. Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York, USA.

    • Joseph J C Thome
    •  & Donna L Farber
  3. Department of Surgery, Columbia University Medical Center, New York, New York, USA.

    • Yoshiaki Ohmura
    • , Masaru Kubota
    • , Nobuhide Matsuoka
    • , Tomoaki Kato
    •  & Donna L Farber
  4. Department of Medicine, Columbia University Medical Center, New York, New York, USA.

    • Claire Gordon
  5. LiveOnNY, New York, New York, USA.

    • Harvey Lerner

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Contributions

J.J.C.T. designed experiments, generated and analyzed data from infant and adult donor tissues, made figures and wrote and edited the paper; K.L.B. generated phenotypic and functional data from infant donors, analyzed data and made figures; Y.O., M.K., N.M. and A.G. obtained the tissues from organ donors for these studies; C.G. and T.G. assisted with the processing of donor tissue; H.L. coordinated the tissue donation and acquisition from adult donors; T.K. coordinated acquisition for all infant donors; D.L.F. designed experiments, analyzed data, maintained protocols for human tissue acquisition and wrote and edited the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Donna L Farber.

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DOI

https://doi.org/10.1038/nm.4008

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