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

Benlalam, Houssem; Carre, Thibault; Jalil, Abdelali; Noman, Zaeem; Caillou, Bernard; Vielh, Philippe; Tittarelli, Andres; Robert, Caroline; Chouaib, Salem

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-gamma) 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-gamma 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(+)-na ve 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(+)-na ve T lymphocyte activation.

Más información

Título según WOS: ID WOS:000324673300009 Not found in local WOS DB
Título de la Revista: JOURNAL OF MOLECULAR MEDICINE-JMM
Volumen: 91
Número: 10
Editorial: Springer
Fecha de publicación: 2013
Página de inicio: 1207
Página final: 1220
DOI:

10.1007/s00109-013-1058-5

Notas: ISI