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  • Phone : +33 6 80 70 64 16
  • Location : Paris, France
Last update 2012-07-26 12:03:05.772

Sophie Caillat-Zucman Professor Immunology

Course and current status

1982-1988:Residency (Nephrology), Hopitaux de Paris

1988-1992:Assistant in Immunology (junior staff), Hopital Necker-University Paris 5

1992-2011:Assistant-Professor of Immunology (MCU-PH), University Paris 5 and Head of the Histocompatibility Laboratory, Hopital Necker, Paris


2002-2006: Director of AVENIR Team, INSERM

2011-present: Professor of Immunology (PU-PH) University Paris 7-Hôpital Robert Debré



Scientific summary

During the last 10years, my group has been characterizing disease-associated mechanisms leading to abnormal NKG2D expression and inappropriate immune response triggering.NKG2D is an activating receptor expressed on NK and CD8 T cells, and under certain conditions on CD4 T cells. NKG2D binds to a variety of ligands (MICs and ULBPs in humans) expressed on diseased or stressed cells, resulting in potent effector cell-mediated cytotoxicity and cytokine production. The in vivo importance of the NKG2D surveillance mechanism in immune responses is underscored by evasion measures taken by viruses and tumors to avoid NKG2D triggering. On the other hand, aberrant expression of NKG2D or its ligands has been implicated in the pathogenesis of autoimmune diseases. 

We intially reported the crucial role of the NKG2D pathway in the destruction of intestinal epithelium by intraepithelial CD8 T lymphocytes (IEL) in celiac disease. We showed that villous atrophy could be ascribed to a TCR-independent, innate-like cytotoxicity of IELs towards gut epithelial expresseing MICA upon gliadin and IL-15 expression. We also demonstrated the deleterious effect of combined IL-15 and MICA overexpression in granulomatosis with polyangiitis (former Wegener’s disease). We showed that excessive IL-15 production and expression of MICA on monocytes induced aberrant expansions of innate-like NKG2D+ CD4 T lymphocytes capable to exert TCR-independent cytotoxicity towards microvascular endothelial cells, and to mediate endothelium damage in this disease

In parallel, we identified the downmodulation of NKG2D as a mechanism used by persistent viruses (HCV and HHV8) to escape NK cell response, through viral-mediated production of immunomodulators. We showed that HCV-NS5A stimulation of monocytes through TLR4 promoted secretion of TGFb, which downmodulated NKG2D expression on NK cells from HCV patients, leading to their impaired cytotoxic capacity and IFNg production. IL-15 could antagonize TGFb and restore normal NKG2D expression on NKcells. We next characterized prostaglandin E2 (PGE2), released by HHV8-infected cells, as responsible for downmodulation of NKG2D and inhibition of IL-15-mediated NK cell activation. This points to COX2/PGE2 inhibitors as additional tool to treat aggressive Kaposi sarcoma,as they could restore activation and survival of tumoricidal NK cells.

Altogether, our results illustrate that selectively modulating NKG2D expression, and thereby the function of cytotoxic lymphocytes, may provide many opportunities to influence the outcome of infectious diseases, cancer, and certain autoimmune diseases.

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