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ICAM-1–Dependent Homotypic Aggregates Regulate CD8 T Cell Effector Function and Differentiation during T Cell Activation

Nicholas A. Zumwalde, Eisuke Domae, Matthew F. Mescher and Yoji Shimizu
J Immunol October 1, 2013, 191 (7) 3681-3693; DOI: https://doi.org/10.4049/jimmunol.1201954
Nicholas A. Zumwalde
Department of Laboratory Medicine and Pathology, Center for Immunology, Masonic Cancer Center, University of Minnesota Medical School, Minneapolis, MN 55455
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Eisuke Domae
Department of Laboratory Medicine and Pathology, Center for Immunology, Masonic Cancer Center, University of Minnesota Medical School, Minneapolis, MN 55455
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Matthew F. Mescher
Department of Laboratory Medicine and Pathology, Center for Immunology, Masonic Cancer Center, University of Minnesota Medical School, Minneapolis, MN 55455
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Yoji Shimizu
Department of Laboratory Medicine and Pathology, Center for Immunology, Masonic Cancer Center, University of Minnesota Medical School, Minneapolis, MN 55455
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Abstract

A hallmark of T cell activation in vitro and in vivo is the clustering of T cells with each other via interaction of the LFA-1 integrin with ICAM-1. The functional significance of these homotypic aggregates in regulating T cell function remains unknown. We used an APC-free in vitro activation system to demonstrate that stimulation of purified naive CD8 T cells results in enhanced expression of ICAM-1 on T cells that is sustained by the inflammatory cytokine IL-12 and associated with robust T cell aggregates. ICAM-1–deficient CD8 T cells proliferate normally but demonstrate a striking failure to aggregate. Interestingly, loss of ICAM-1 expression results in elevated levels of IFN-γ and granzyme B, as well as enhanced cytotoxicity. Similar results were obtained when anti–LFA-1 Ab was used to block the clustering of wild-type T cells. ICAM-1 ligation is not required for IFN-γ regulation, as clustering of ICAM-1–deficient CD8 T cells with wild-type T cells reduces IFN-γ expression. Analysis using a fluorescent reporter that monitors TCR signal strength indicates that T cell clustering limits T cell exposure to Ag during activation. Furthermore, T cell clustering promotes the upregulation of the CTLA-4 inhibitory receptor and the downregulation of eomesodermin, which controls effector molecule expression. Activation of ICAM-1–deficient CD8 T cells in vivo results in an enhanced percentage of KLRG-1+ T cells indicative of short-lived effectors. These results suggest that T cell clustering represents a mechanism that allows continued proliferation but regulates T cell effector function and differentiation.

Footnotes

  • This work is supported by National Institutes of Health Grants R01 AI038474 (to Y.S.) and T32 CA009138 (to N.A.Z.) and by pilot funding from a Cancer Center support grant at the Masonic Cancer Center, University of Minnesota (to Y.S.).

  • The online version of this article contains supplemental material.

  • Abbreviation used in this article:

    DC
    dendritic cell
    PD-1
    programmed death 1
    PD-L1
    programmed death ligand 1.

  • Received July 13, 2012.
  • Accepted August 5, 2013.
  • Copyright © 2013 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 191 (7)
The Journal of Immunology
Vol. 191, Issue 7
1 Oct 2013
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ICAM-1–Dependent Homotypic Aggregates Regulate CD8 T Cell Effector Function and Differentiation during T Cell Activation
Nicholas A. Zumwalde, Eisuke Domae, Matthew F. Mescher, Yoji Shimizu
The Journal of Immunology October 1, 2013, 191 (7) 3681-3693; DOI: 10.4049/jimmunol.1201954

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ICAM-1–Dependent Homotypic Aggregates Regulate CD8 T Cell Effector Function and Differentiation during T Cell Activation
Nicholas A. Zumwalde, Eisuke Domae, Matthew F. Mescher, Yoji Shimizu
The Journal of Immunology October 1, 2013, 191 (7) 3681-3693; DOI: 10.4049/jimmunol.1201954
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