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Osteopontin and iCD8α Cells Promote Intestinal Intraepithelial Lymphocyte Homeostasis

Ali Nazmi, Michael J. Greer, Kristen L. Hoek, M. Blanca Piazuelo, Joern-Hendrik Weitkamp and Danyvid Olivares-Villagómez
J Immunol April 1, 2020, 204 (7) 1968-1981; DOI: https://doi.org/10.4049/jimmunol.1901168
Ali Nazmi
*Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232;
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Michael J. Greer
†Department of Biomedical Informatics, Vanderbilt University, Nashville, TN 37232;
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Kristen L. Hoek
*Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232;
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M. Blanca Piazuelo
‡Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232;
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Joern-Hendrik Weitkamp
§Department of Pediatrics, Vanderbilt University Medical Center, Monroe Carell Jr. Children’s Hospital, Nashville, TN 37232; and
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Danyvid Olivares-Villagómez
*Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232;
¶Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University Medical Center, Nashville, TN 37232
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Key Points

  • Osteopontin promotes homeostasis of mouse and human IEL, mediated by its ligand CD44.

  • iCD8α cells produce osteopontin, which impacts the survival of other IEL.

  • Lack of osteopontin renders mice susceptible to intestinal inflammation.

Abstract

Intestinal intraepithelial lymphocytes (IEL) comprise a diverse population of cells residing in the epithelium at the interface between the intestinal lumen and the sterile environment of the lamina propria. Because of this anatomical location, IEL are considered critical components of intestinal immune responses. Indeed, IEL are involved in many different immunological processes, ranging from pathogen control to tissue stability. However, despite their critical importance in mucosal immune responses, very little is known about the homeostasis of different IEL subpopulations. The phosphoprotein osteopontin is important for critical physiological processes, including cellular immune responses, such as survival of Th17 cells and homeostasis of NK cells among others. Because of its impact in the immune system, we investigated the role of osteopontin in the homeostasis of IEL. In this study, we report that mice deficient in the expression of osteopontin exhibit reduced numbers of the IEL subpopulations TCRγδ+, TCRβ+CD4+, TCRβ+CD4+CD8α+, and TCRβ+CD8αα+ cells in comparison with wild-type mice. For some IEL subpopulations, the decrease in cell numbers could be attributed to apoptosis and reduced cell division. Moreover, we show in vitro that exogenous osteopontin stimulates the survival of murine IEL subpopulations and unfractionated IEL derived from human intestines, an effect mediated by CD44, a known osteopontin receptor. We also show that iCD8α IEL but not TCRγδ+ IEL, TCRβ+ IEL, or intestinal epithelial cells, can promote survival of different IEL populations via osteopontin, indicating an important role for iCD8α cells in the homeostasis of IEL.

Footnotes

  • This work was supported by National Institutes of Health (NIH) Grant R01DK111671 (to D.O.-V.), Careers in Immunology Fellowship Program from the American Association of Immunologists (to D.O.-V. and A.N.), National Library of Medicine Grant T15 LM00745 (to M.J.G.), scholarships from the Digestive Disease Research Center at Vanderbilt University Medical Center, supported by NIH Grant P30DK058404, and the Vanderbilt Genome Editing Resource, supported by a Diabetes Research and Training Center Grant (DK020593) and Vanderbilt-Ingram Cancer Center Support Grant (CA68485).

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article:

    7AAD
    7-aminoactinomycin D
    GSEA
    gene set enrichment analysis
    IBD
    inflammatory bowel disease
    iCD3+
    intracellular CD3γ-chain
    iCD8α cell
    iCD3+ expressing CD8αα
    IEC
    intestinal epithelial cell
    IEL
    intraepithelial lymphocyte
    ILC
    innate lymphoid cell
    SPP
    secreted phosphoprotein
    Vill
    villin
    WT
    wild-type.

  • Received September 23, 2019.
  • Accepted January 23, 2020.
  • Copyright © 2020 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 204 (7)
The Journal of Immunology
Vol. 204, Issue 7
1 Apr 2020
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Osteopontin and iCD8α Cells Promote Intestinal Intraepithelial Lymphocyte Homeostasis
Ali Nazmi, Michael J. Greer, Kristen L. Hoek, M. Blanca Piazuelo, Joern-Hendrik Weitkamp, Danyvid Olivares-Villagómez
The Journal of Immunology April 1, 2020, 204 (7) 1968-1981; DOI: 10.4049/jimmunol.1901168

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Osteopontin and iCD8α Cells Promote Intestinal Intraepithelial Lymphocyte Homeostasis
Ali Nazmi, Michael J. Greer, Kristen L. Hoek, M. Blanca Piazuelo, Joern-Hendrik Weitkamp, Danyvid Olivares-Villagómez
The Journal of Immunology April 1, 2020, 204 (7) 1968-1981; DOI: 10.4049/jimmunol.1901168
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