NK cell regulation of CD4 T cell-mediated graft-versus-host disease

CD3-negative NK cells are granular lymphocytes capable of producing inflammatory cytokines and killing malignant, infected, or stressed cells. We have recently observed a new role for NK cells in the control of the proliferation of CD4 T cells under persistent antigenic stimulation. Monoclonal anti-...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2010-06, Vol.184 (12), p.6790-6798
Main Authors: Noval Rivas, Magali, Hazzan, Marc, Weatherly, Kathleen, Gaudray, Florence, Salmon, Isabelle, Braun, Michel Y
Format: Article
Language:English
Subjects:
Adoptive Transfer
Animals
CD4-Positive T-Lymphocytes - immunology
Cell Proliferation
Cell Separation
Female
Flow Cytometry
Graft vs Host Disease - immunology
Killer Cells, Natural - immunology
Lymphocyte Activation - immunology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
NK Cell Lectin-Like Receptor Subfamily K - immunology
Reverse Transcriptase Polymerase Chain Reaction
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Summary:CD3-negative NK cells are granular lymphocytes capable of producing inflammatory cytokines and killing malignant, infected, or stressed cells. We have recently observed a new role for NK cells in the control of the proliferation of CD4 T cells under persistent antigenic stimulation. Monoclonal anti-male CD4 T cells transferred into Rag2-/- male recipients did not expand or were rapidly eliminated. Remarkably, T cells transferred into NK cell-deficient Rag2-/- Il-2Rgammac-/- male hosts expanded extensively and mediated tissue lesions usually observed in chronic graft-versus-host disease (GVHD). T cell failure to proliferate and to induce chronic GVHD was the result of NK cell activity, because depletion of the recipient's NK1.1+ cells by Ab treatment induced T cell expansion and chronic GVHD. T cells under chronic Ag stimulation upregulated ligands of the activating receptor NKG2D, and regulatory activity of NK cells was inhibited by the injection of Abs directed to NKG2D. On the contrary, blocking NKG2A inhibitory receptors did not increase NK cell regulatory activity. Finally, we show that NK regulation of T cell expansion did not involve perforin-mediated lytic activity of NK cells, but depended on T cell surface expression of a functional Fas molecule. These results highlight the potential role played by NK cells in controlling the Ag-specific CD4+ T cells responsible for chronic GVHD.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.0902598