NKp80 defines and stimulates a reactive subset of CD8 T cells

Kuttruff, Sabrina; Koch, Sven D.; Kelp, Alexandra; Pawelec, Graham; Rammensee, Hans‐Georg; Steinle, Alexander

doi:10.1182/blood-2008-03-145615

Cited by 47 publications

(43 citation statements)

References 49 publications

(75 reference statements)

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“…Moreover, AICL receptor expressed on myeloid cells and NKp80 expressed on NK and memory CD8 ϩ T cells are both activating C-type lectin-like receptors interacting with each other, and their mutual engagement promotes reciprocal activation and cytokine release at sites of inflammation (36). CLEC-1 triggering may modulate directly activation of the DCs and ECs and/or give a regulatory signal to T cells.…”

Section: Discussionmentioning

confidence: 99%

The C-Type Lectin-Like Receptor CLEC-1, Expressed by Myeloid Cells and Endothelial Cells, Is Up-Regulated by Immunoregulatory Mediators and Moderates T Cell Activation

Thébault

Lhermite

Tilly

et al. 2009

The Journal of Immunology

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C-type lectin receptors have recently been described as playing crucial roles in immunity and homeostasis since these proteins are able to recognize pathogens as well as self-Ags. We identified the C-type lectin-like receptor-1, CLEC-1, as being overexpressed in a model of rat allograft tolerance. We previously described in this model the expression of numerous cytoprotective molecules by graft endothelial cells and their interplay with regulatory CD4+CD25+ T cells. In this study, we demonstrate that CLEC-1 is expressed by myeloid cells and specifically by endothelial cells in tolerated allografts and that CLEC-1 expression can be induced in endothelial cells by alloantigen-specific regulatory CD4+CD25+ T cells. Analysis of CLEC-1 expression in naive rats demonstrates that CLEC-1 is highly expressed by myeloid cells and at a lower level by endothelial cells, and that its expression is down-regulated by inflammatory stimuli but increased by the immunoregulators IL-10 or TGFβ. Interestingly, we demonstrate in vitro that inhibition of CLEC-1 expression in rat dendritic cells increases the subsequent differentiation of allogeneic Th17 T cells and decreases the regulatory Foxp3+ T cell pool. Additionally, in chronically rejected allograft, the decreased expression of CLEC-1 is associated with a higher production of IL-17. Taken together, our data suggest that CLEC-1, expressed by myeloid cells and endothelial cells, is enhanced by regulatory mediators and moderates Th17 differentiation. Therefore, CLEC-1 may represent a new therapeutic agent to modulate the immune response in transplantation, autoimmunity, or cancer settings.

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Section: Discussionmentioning

confidence: 99%

The C-Type Lectin-Like Receptor CLEC-1, Expressed by Myeloid Cells and Endothelial Cells, Is Up-Regulated by Immunoregulatory Mediators and Moderates T Cell Activation

Thébault

Lhermite

Tilly

et al. 2009

The Journal of Immunology

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“…NKp80 is an activating receptor of human NK cells and some T cells (3)(4)(5); however, in contrast to many other NKRs, the molecular mechanisms of signal transduction by NKp80 are completely unknown. To dissect NKp80 signaling, we sought a suitable NK cell line for reconstitution experiments.…”

Section: Tyrosine 7 Of Nkp80 Is Phosphorylated and Required For Nk Cymentioning

confidence: 99%

“…Like NKG2D, NKp80 is an activating homodimeric C-type lectin-like receptor encoded in the natural killer gene complex (3). NKp80 binds to the genetically linked activation-induced C-type lectin (AICL) and, thereby, stimulates NK cytotoxicity against malignant myeloid cells, promotes a mutual cross-talk between NK cells and monocytes, but also augments responses of effector memory CD8 T cells (4,5).…”

mentioning

confidence: 99%

Cutting Edge: NKp80 Uses an Atypical Hemi-ITAM To Trigger NK Cytotoxicity

Dennehy

Klimosch

Steinle

2011

The Journal of Immunology

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The human NK cell receptor NKp80 stimulates cytotoxicity upon engagement of its genetically linked ligand AICL. However, the mechanisms underlying NKp80-mediated signaling are unknown. In this study, we dissected NKp80 signaling using the NK cell line NK92MI. We demonstrated that NKp80, but not NKp80 mutated at tyrosine 7 (NKp80/Y7F), is tyrosine phosphorylated. Accordingly, NKp80/Y7F, but not NKp80/Y30F or NKp80/Y37F, failed to induce cytotoxicity. NKp80 phosphopeptides comprising the hemi-ITAM–like sequence surrounding tyrosine 7 bound Lck- and Syk-family kinases; accordingly, cross-linking of NKp80, but not NKp80/Y7F, induced Syk phosphorylation. Moreover, inhibition of Syk kinase, but not ZAP-70 kinase, impaired cytotoxic responses through NKp80. Atypical residues in the hemi-ITAM–like motif of NKp80 cause an altered stoichiometry of phosphorylation but did not substantially affect NK cytotoxicity. Altogether, these results show that NKp80 uses an atypical hemi-ITAM and Syk kinase to trigger cellular cytotoxicity.

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“…NKp80 (encoded by KLRF1) is a type II transmembrane CTLR expressed as a disulfide-linked homodimer on human peripheral blood NK cells (76) and a subset of effector memory T cells (77). NKp80 binds to the C-type lectin-like glycoprotein AICL that is encoded adjacently to the KLRF1 locus in the NKC and present on myeloid cells (78) and monokine-experienced NK cells (79).…”

Section: Nkp80mentioning

confidence: 99%