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

Research output: Contribution to journalArticle

26 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3681-3693
Number of pages13
JournalJournal of Immunology
Volume191
Issue number7
DOIs
StatePublished - Oct 1 2013

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Intercellular Adhesion Molecule-1
T-Lymphocytes
Cluster Analysis
Lymphocyte Function-Associated Antigen-1
Granzymes
Interleukin-12
Integrins

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ICAM-1-dependent homotypic aggregates regulate CD8 T cell effector function and differentiation during T cell activation. / Zumwalde, Nicholas A.; Domae, Eisuke; Mescher, Matthew F.; Shimizu, Yoji.

In: Journal of Immunology, Vol. 191, No. 7, 01.10.2013, p. 3681-3693.

Research output: Contribution to journalArticle

Zumwalde, Nicholas A. ; Domae, Eisuke ; Mescher, Matthew F. ; Shimizu, Yoji. / ICAM-1-dependent homotypic aggregates regulate CD8 T cell effector function and differentiation during T cell activation. In: Journal of Immunology. 2013 ; Vol. 191, No. 7. pp. 3681-3693.
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