Gamma-delta T lymphocytes in anti-viral and anti-tumor immunity
Our team is dedicated to understand the bioactivity and the activation modalities of gamma-delta T cells. Gamma-delta T cells are T lymphocytes at the interface between innate and adaptive immunity. They preferentially localize in epithelia where they represent a major population of intraepithelial T lymphocytes (IEL). Gamma-delta T cells can respond to stressed, infected or transformed cells by secreting cytokines (mainly IFNgamma and TNFalpha) and by killing their targets. They are believed to be involved in immune surveillance but their precise functions have remained much more enigmatic than that of conventional alpha-beta T lymphocytes, probably because of their ability to act either as effectors or immunoregulatory cells (depending on circumstances). Our interest in transplantation immunology led us to demonstrate an implication of a subset of gamma-delta T cells (Vdelta2neg gamma-delta T cells) in the immune response to cytomegalovirus (CMV), a common opportunistic pathogen in immunosuppressed individuals. By combining clinical and in vitro investigations, we got insights into the interactions between gamma-delta T cells and their targets: CMV-infected cells but also tumour epithelial cells. Our aim is to clarify the precise role of gamma-delta T cells in the surveillance of viral infection or transformation, and to unravel the molecular recognition of cellular stress signals by gamma-delta T cells on their targets. We plan to achieve these goals through both in vivo studies in mouse models and diverse in vitro approaches.
Our projects are driven by the idea that the acquisition of basic knowledge on gamma-delta T cell biological functions should provide tools for the elaboration of a novel type of anti-viral or anti-tumour immunotherapy.
People involved: Myriam Capone, Lionel Couzi, Julie Déchanet-Merville, Pierre Merville, Sonia Netzer, Angela Pappalardo, Vincent Pitard
People involved: Myriam Capone, Lionel Couzi, Julie Déchanet-Merville, Hannah Kaminski, Layal Massara, Maria Mamani-Matsuda, Pierre Merville, Sonia Netzer, Vincent Pitard
People involved: Valérie Calco, Charlotte Domblides, Benjamin Faustin, Julie Déchanet-Merville.
People involved: Layal Massara, Julie Déchanet-Merville, Pierre Merville, Jonathan Visentin
Knowledge on the role of gamma-delta T cells in humoral response remains fragmented. Germinal center formation and production of class-switched antibodies occurs efficiently in alpha-betaT cell deficient mice (35). Many of the antibodies synthesized in these mice are reactive to a similar spectrum of self-antigens as that targeted by autoantibodies characterizing human SLE. gamma-delta T cells have been shown to provide help for the production of these antibodies (including autoantibodies). In humans, gamma-delta T cells express CD154 and ICOS upon in vitro activation, a subset of gamma-delta T cells with a Tfh profile are found in blood and tonsils, and patients with alpha-beta T cell deficiencies and elevated levels of gamma-delta T cells have normal levels of Igs (36-38). We want to take advantage of gamma-delta T cell response to CMV as a model to study the cooperation between gamma-delta T cells and B cells. Since gamma-delta T cells recognize self-antigens, are they able to activate or to control autoreactive B cells recognizing the same self-antigens? How does this affect or contribute to self tolerance?
by Marie-Désirée Smith
Group leader: Julie Déchanet-Merville
Phosphoantigen burst upon Plasmodium falciparum schizont rupture can distantly activate Vgamma9-Vdelta2 T-cells. Guenot M, Loizon S, Howard J, Costa G, Baker DA, Mohabeer SY, Troye-Blomberg M, Moreau JF, Dechanet-Merville J, Mercereau-Puijalon O, Mamani-Matsuda M and Behr C. Infect Immun. 2015, Oct;83(10):3816-24
Surveillance of γδ T Cells Predicts Cytomegalovirus Infection Resolution in Kidney Transplants. Kaminski H, Garrigue I, Couzi L, Taton B, Bachelet T, Moreau JF, Déchanet-Merville J, Thiébaut R, and Merville P. J Am Soc Nephrol. 2016, Feb;27(2):637-45
TCR-dependent sensitization of human gamma-delta T cells to non-myeloid IL18 in CMV and tumour stress surveillance. Guerville F, Daburon S, Marlin R, Lartigue L, Loizon S, Pitard V, Couzi L, Moreau JF, Déchanet-Merville J and Faustin B, Oncoimmunology 2015, Feb 3;4(5):e1003011
Gamma-delta T Cells Confer Protection against Murine Cytomegalovirus (MCMV). Khairallah C, Netzer, Villacreces A, Juzan M, Rousseau B, Dulanto S, Giese A, Costet P, Praloran V, Moreau JF, Dubus P, Vermijlen D, Déchanet-Merville J and Capone M. Plos Pathogens (2015) Mar 6;11(3):e1004702.
Cytomegalovirus-responsive gamma-delta T cells: novel effector cells in antibody-mediated kidney allograft microcirculation lesions. Bachelet T, Couzi L, Pitard V, Sicard X, Rigothier C, Lepreux S, Moreau JF, Taupin JL, Merville P, Déchanet-Merville J. J Am Soc Nephrol. (2014) Nov;25(11):2471-82.
Anti-metastatic potential of human Vdelta1+ gamma-delta T cells in an orthotopic mouse xenograft model of colon carcinoma. Devaud C, Rousseau B, Netzer S, Pitard V, Paroissin C, Khairallah C, Costet P, Moreau JF, Couillaud F, Dechanet-Merville J and Capone M. Cancer Immunol Immunother (2013) Jul;62(7):1199-210.
CMV and tumor stress-surveillance by human gamma-delta T cell receptor binding to Endothelial Protein C Receptor. Willcox C*, Pitard V*, Netzer S, Couzi L, Salim M, Silberzahn T, Moreau JF, Hayday A, Willcox B*, and Déchanet-Merville J*. *equal contributors Nat Immunol (2012) 13: 872-879. News and Views on this paper p813-814.
Antibody-dependent anti-cytomegalovirus activity of human gamma-delta T cells expressing CD16 (FcgammaRIIIa). Couzi L, Pitard V, Sicard, X, Garrigue I, Hawchar O, Merville P, JF Moreau and Déchanet-Merville J. Blood (2012) 119:1418-27.
Control of Plasmodium falciparum erythrocytic cycle: γδ T cells target the red blood cell-invasive merozoites. Costa G, Loizon S, Guenot M, Mocan I, Halary F, de Saint-Basile G, Pitard V, Déchanet-Merville J, Moreau JF, Troye-Blomberg M, Mercereau-Puijalon O and Behr C. Blood (2011) Dec 22;118(26):6952-62.
CMV-induced gamma-delta T cells associate with reduced cancer risk after kidney transplantation. Couzi L, Levaillant Y, Jamai A, Pitard V, Lassalle R, Martin K, Garrigue I, Hawchar O, Siberchicot F, Moore N, Moreau J-F, Dechanet-Merville J and Merville P. J Am Soc Nephrol. (2010) 21: 181-188. Editorial on this paper p11-13
Common features of gamma-delta T cells and CD8+ alpha-beta T cells responding to human Cytomegalovirus infection in kidney transplant recipients. Couzi L, Pitard V, Netzer S, Garrigue I, Lafon M-E, Moreau J-F, Taupin J-L, Merville P and Déchanet-Merville J. J. Infect. Dis. (2009) 200 : 1415–1424
Anti-tumor activity of gamma-delta T cells reactive against cytomegalovirus-infected cells in a mouse xenograft tumor model. Devaud C, Bilhère E, Loizon S, Pitard V, Behr C, Moreau J-F, Déchanet-Merville J and Capone M. Cancer Research, (2009) 69: 3971-3978.
Long term expansion of effector/memory Vdelta2neg gamma-delta T cells is a specific blood signature of CMV infection. Pitard V, Roumanes D, Lafarge X, Couzi L, Garrigue I, Lafon M-E, Merville P, Moreau JF and Déchanet-Merville J. Blood (2008) 112: 1317-1324.
Expression of MHC-Class I receptors confers functional intraclonal heterogeneity to a reactive expansion of gamma-delta T cells. Lafarge X, Pitard V, Ravet S, Roumanes D, Halary F, Dromer C, Vivier E, Paul P, Moreau JF, Déchanet-Merville J. Eur. J. Immunol. (2005) 35: 1896-1905.
Shared reactivity of Vdelta2neg gamma-delta T cells against CMV-infected cells and tumor intestinal epithelial cells. Halary F, Pitard V, Dlubek D, Krzysiek R, de la Salle H, Merville P, Dromer C, Emilie D, Moreau JF and Déchanet-Merville J. J. Exp. Med. (2005) 201: 1567-1578. Commentary on this paper p. 1521
Human cytomegalovirus binding to DC-SIGN is required for dendritic cell infection and target cell trans-infection. Halary F, Amara A, Lortat-Jacob H, Messerle, Delaunay T, Houlès C, Fieschi F, Arenzana-Seisdedos F, Moreau J-F, Déchanet-Merville J. Immunity (2002) 17: 653-664. « Highlight » on this paper in Nature Review Immunol. (2003, 3:8)
Reviews & Editorials
Direct and Indirect Effects of Cytomegalovirus-induced gd T Cells after Kidney Transplantation. Couzi L, Pitard V, Merville P, Moreau JF and Déchanet-Merville J, Frontiers in Immunology (2015) Jan 21;6:3.
Promising cell-based immunotherapy using gamma delta T cells: together is better.Déchanet-Merville J. Clin Cancer Res. (2014) Nov 15;20(22):5573-5.
Harnessing γδ T cells in anticancer immunotherapy. Hannani D, Ma Y, Yamazaki T, Déchanet-Merville J, Kroemer G and Zitvogel L. Trends in Immunology (2012) 33: 199-206.
Vdelta2-negative gamma-delta T cells, a multi-reactive tissue subset : from innate to adaptive altered-self surveillance. Behr C, Capone M, Couzi L, Taupin JL and Déchanet-Merville Open Immunol J. (2009) 2 : 106-118
- Laurent Genestier (CRBL, Lyon)
- Olivier Thaunat (CIRI, Lyon)
- Emmanuel Scotet (CRCNA, Nantes)
- Odile Mercereau-Puijalon (Institut Pasteur, Paris)
- Gavin Wilkinson & Ceri Fieldings (Division of Infection and Immunity, Cardiff University)
- Bernhard Moser & Matthias Eberl (Division of Infection and Immunity, Cardiff University)
- Benjamin Willcox (CRUK Cancer Centre Institute of Immunology and Immunotherapy, Birmingham)
- David Vermijlen (Institute for Medical Immunology (IMI), Université Libre de Bruxelles )
- Bruno Silva-Santos (Instituto de Medicina Molecular, Lisbon)
- Carlos Vilches (Hospital Univ. Puerta de Hierro, Madrid)
- Paul Fisch (Institut für Klinische Pathologie, Frieburg)
- Ralph Budd (The University of Vermont College of Medicine, Burlington)
- Mark Davis (Stanford, California)