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J Mol Med (Berl). 2013 Oct;91(10):1207-20. doi: 10.1007/s00109-013-1058-5. Epub 2013 Jun 7.

Regulation of gap junctions in melanoma and their impact on Melan-A/MART-1-specific CD8⁺ T lymphocyte emergence.

Author information

1
Institut National de la Santé et de la Recherche Médicale (INSERM U753), Institut Fédératif de Recherche 54 (IFR54), Institut Gustave Roussy, 39 Rue Camille Desmoulins, 94805, Villejuif, France.

Abstract

Gap junctions (GJs) enable intercellular communication between adjacent cells through channels of connexins. Using a three-dimensional construct, we previously showed that endothelial and tumor cells formed GJs, allowing melanoma-specific T lymphocytes to recognize and kill melanoma-derived endothelial cells. We demonstrate here on histological sections of melanoma biopsies that GJ formation occurs in vivo between tumor and endothelial cells and between T lymphocytes and target cells. We also show an in vitro increase of GJ formation in melanoma and endothelial cells following dacarbazin and interferon gamma (IFN-γ) treatment or hypoxic stress induction. Our data indicate that although connexin 43 (Cx43), the main GJ protein of the immune system, was localized at the immunological synapse between T lymphocyte and autologous melanoma cells, its over-expression or inhibition of GJs does not interfere with cytotoxic T lymphocyte (CTL) clone lytic function. In contrast, we showed that inhibition of GJs by oleamide during stimulation of resting PBMCs with Melan-A natural and analog peptides resulted in a decrease in antigen (Ag) specific CD8(+) T lymphocyte induction. These Ag-specific CD8(+) cells displayed paradoxically stronger reactivity as revealed by CD107a degranulation and IFN-γ secretion. These findings indicate that Cx43 does not affect lytic function of differentiated CTL, but reveal a major role for GJs in the regulation of antigen CD8(+)-naïve T lymphocyte activation.

KEY MESSAGE:

GJ formation occurs in vivo between T lymphocytes and tumor cells Cx43 localized at the immunological synapse between T and autologous melanoma cells Inhibition of GJs resulted in a decrease in Ag-specific CD8(+) T lymphocyte induction A role for GJs in the regulation of antigen CD8(+)-naïve T lymphocyte activation.

PMID:
23744108
DOI:
10.1007/s00109-013-1058-5
[Indexed for MEDLINE]

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