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Mucosal memory CD8+ T cells are selected in the periphery by an MHC class I molecule

Nature Immunology volume 12, pages 1086–1095 (2011)Cite this article

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Abstract

The presence of immune memory at pathogen-entry sites is a prerequisite for protection. Nevertheless, the mechanisms that warrant immunity at peripheral interfaces are not understood. Here we show that the nonclassical major histocompatibility complex (MHC) class I molecule thymus leukemia antigen (TL), induced on dendritic cells interacting with CD8αα on activated CD8αβ+ T cells, mediated affinity-based selection of memory precursor cells. Furthermore, constitutive expression of TL on epithelial cells led to continued selection of mature CD8αβ+ memory T cells. The memory process driven by TL and CD8αα was essential for the generation of CD8αβ+ memory T cells in the intestine and the accumulation of highly antigen-sensitive CD8αβ+ memory T cells that form the first line of defense at the largest entry port for pathogens.

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Figure 1: TL negatively affects the generation of memory cells from CD8αβ+ T cells.
Figure 2: TL mediates the death of activated CD8αβ+ T cells.
Figure 3: Activation-induced CD8αα rescues CD8αβ+ primary effector T cells from TL-induced cell death.
Figure 4: CD8αα expression correlates with the intensity of TCR activation.
Figure 5: CD8αα expression marks effector memory CD8αβ+ T cells in humans.
Figure 6: Retinoic acid promotes the affinity-based accumulation of CD8αα+CD8αβ+ T cells in the intestine.
Figure 7: Constitutive expression of TL on intestinal epithelial cells mediates the selection of mature memory CD8αβ+ T cells.

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Acknowledgements

We thank M.J. Bevan (University of Washington) for LM-N4 and LM-Q4; E. Stockert and L. Old (Memorial Sloan-Kettering) for anti-TL (HD168); M. Cheroutre for contributions; L. Qiao, X.Z. Wang and members of the Cheroutre and Kronenberg laboratories for discussions and technical assistance; and D. Littman (New York University School of Medicine) for ΔE8I mice. Supported by the US National Institutes of Health (R01 AI064584 and R01 AI050265 to H.C.; R01 AG10152 to M.K. and H.C.; and CA009385 to D.O.-V.), the Vanderbilt University Digestive Disease Research Center and the Vanderbilt-Meharry Center for AIDS Research (L.V.K.), the Austrian Science Fund (Project S9308-B05 to B.G.-L.) and the Austrian Federal Ministry of Science and Research (Future Leaders of Ageing Research in Europe; D.H.-B.). This is manuscript 1063 from the La Jolla Institute for Allergy & Immunology.

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Author notes

  1. Iván Bernardo

    Present address: Present address: Clinical Laboratory. Histocompatibility Section, San Pedro Hospital, Logroño, Spain.,

  2. Yujun Huang and Yunji Park: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Developmental Immunology, La Jolla Institute for Allergy & Immunology, La Jolla, California, USA

    Yujun Huang, Yunji Park, Yiran Wang-Zhu, Alexandre Larange, Ramon Arens, Iván Bernardo, Stephen P Schoenberger, Mitchell Kronenberg & Hilde Cheroutre

  2. Department of Microbiology & Immunology, Vanderbilt University, School of Medicine, Nashville, Tennessee, USA

    Danyvid Olivares-Villagómez & Luc Van Kaer

  3. Division of Immunology, Institute for Biomedical Aging Research, Austrian Academy of Sciences, Innsbruck, Austria

    Dietmar Herndler-Brandstetter & Beatrix Grubeck-Loebenstein

  4. Department of Microbiology and Immunology, Life Sciences Institute, Vancouver, Canada

    Ninan Abraham

  5. Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA

    Michael A Teitell

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Contributions

Y.H. and Y.P., conceptual development and execution of the studies and preparation of the manuscript; Y.W.-Z., A.L., R.A. and I.B., technical assistance and input into data analyses; D.O.-V. and L.V.K., generation of TL-deficient mice; M.A.T., generation and backcrossing of TL-transgenic mice; D.H.-B. and B.G.-L., experiments with human samples; N.A., mice with mutation in the sequence encoding IL-7Rα Y449XXM; S.P.S., help with in vitro culture experiments; M.K., participation in discussions of the data and preparation of the manuscript; H.C., conception of ideas, generation of TL transgenic mice with the assistance of M.A.T., manuscript authorship and experiment supervision.

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Correspondence to Hilde Cheroutre.

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Huang, Y., Park, Y., Wang-Zhu, Y. et al. Mucosal memory CD8+ T cells are selected in the periphery by an MHC class I molecule. Nat Immunol 12, 1086–1095 (2011). https://doi.org/10.1038/ni.2106

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