Interactions between regulatory T cells and Plasmacytoid Dendritic cells
Christophe Caux, PhD
Leader of the Team: Oncogenesis and Tumor Progression
INSERM U590
Centre Léon Bérard-Lyon, France
Time: 2010, monday the 14th of June, 10.30
Place: Pavillon 9, etage 4, Herlev University Hospital, Herlev Ringvej 75, DK-2730 Herlev
It would be nice to welcome you all
Professor Inge Marie Svane, M.D.
Director
Abstract
Interactions between Treg and plasmacytoid DC: a role in breast cancer immune tolerance
J. Faget, V. Sisirak, M. Gobert, M. Manuel, I. Le Mercier, I. Labidi, I. Treilleux, T. Bachelot, S. Goddard-Léon, J.Y. Blay, I Puisieux, C. Ménétrier-Caux, N. Bendriss-Vermare, C. Caux. Centre Léon Bérard, Equipe "Cytokines et Cancers", INSERM U-590, Lyon Cedex 08, France
Through immunohistochemical analysis of Foxp3 expression in primary breast tumors, we demonstrated that the presence of functional tumor-associated Treg (Ta-Treg) within lymphoid infiltrates was predictive of relapse and death. The high infiltration by CD4+CD25highCD127lowFoxp3+ Ta-Treg could be explained by a CCR4 mediated recruitment. Furthermore, we demonstrated selective Ta-Treg local activation (ICOS+) and proliferation (KI67+) in lymphoid aggregates, in contrast to other infiltrating T cells and circulating Treg. Indeed, Ta-Treg displayed a restricted TCR repertoire, suggesting specific recognition of tumor-associated antigens.
Moreover, we previously reported that infiltration of breast carcinoma by plasmacytoid Dendritic Cells (pDC) was also associated with an adverse clinical outcome (Treilleux 2004). Human breast tumor-associated pDC (Ta-pDC) have a lower capacity to produce IFN? in response to Toll Like Receptors (TLR) ligands. This alteration was specific to the local tumor microenvironement as pDC from patient blood produced normal IFN? levels and was also observed in mouse mammary tumor models. Of most importance Ta-PDC were selectively altered for cytokine production in response to Toll Like Receptor (TLR)9 ligands while preserving unaltered response to TLR7 ligands. Active TGFb and TNFa, were identified as critical mediators contributing to the alteration of Ta-pDC functions. We further observed that Ta-pDC preserve their capacity to induce T-cell proliferation but direct those T-cells to produce high amounts of the immunosuppressive cytokine IL-10. Finally, several elements suggest interactions between pDC and Treg, possibly involving ICOS/ICOSL within lymphoid aggregates that further promote high levels of IL-10 production by conventional T cells.
Altogether our results demonstrate that human breast tumors promote a tolerogenic immune environment initiated within pseudo-lymphoid structures.
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Last update: June 9, 2010
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