DNA sensing by the immune system in health and disease

 

Our Projects

 Microbial DNA can be detected by multiple innate immune receptors and activate inflammatory responses that are essential for the initiation of antimicrobial immunity. In addition to microbial DNA, innate immune receptors can also detect self-DNA released by dying cells. Recognition of self-DNA may aberrantly stimulate immune responses that can lead to inflammatory disorders and autoimmune diseases. On the other hand, self-DNA released by tumors activates inflammatory responses that are required for the development of anti-tumor immunity. We have characterized a novel nuclease called DNASE1L3 that degrades self-DNA released by dying cells and prevents the development of autoimmune syndromes such as lupus. Given the  tolerogenic role of DNASE1L3 in disposing of self-DNA and thus limiting its immunogenicity we are exploring how its function in multiple pathological contexts.

Beyond the regulation of self-DNA sensing we have developed projects to investigate the mechanisms that regulate anti-tumor immune responses.

Dr. Dorothée Duluc leads this project, in collaboration with Dr. Edouard Forcade (clinician at Haut-Lévêque hospital). The goal is to understand the role of follicular helper cells in CLL pathogenesis and particularly their implication in CLL tumor growth.

This project is developed in collaboration with Dr. Nathalie Schmitt team at Immunoconcept. The goal is to understand how gut microbiota influence anti-tumor immunity induced by immunotherapies. We are hypothesizing that T cells primed in the gut may be recruited to the tumors site and play a crucial role in the induction of anti-tumor immune response.

This project is developed in collaboration with Dr. David Santamaria and the SIRIC BRIO. The goal is to understand how aging may influence the development of tumors and particularly how aging impact cancer surveillance by the immune system and the efficacy of immunotherapies.

Credits: Marie-Désirée Smith

TEAM

Our Team

Vanja Sisirak: Principal Investigator (CRCN, CNRS)
Dorothée Duluc – Assistant Professor (MCF, Université de Bordeaux)
Severine Loizon – Research Engineer (IE, CNRS)
Anne Garreau – Post Doc
Amandine Ferriere – MD/PhD Student
Pauline Santa – PhD Student
Corentin Le Saos Patrinos – PhD Student

PUBLICATIONS

Publication list

Selectins impair regulatory T cell function and contribute to systemic lupus erythematosus pathogenesis. Scherlinger M, Guillotin V, Douchet I, Vacher P, Boizard A, Guegan J.P, Garreau A, Merillon N, Vermorel A, Ribeiro E, Machelart I, Lazaro E, Couzi L, Duffau P, Barnetche T, Pellegrin J.L, Viallard J.F, Saleh M, Schaeverbeke T, Truchetet M.E, Contin-Bordes C, Legembre P, Sisirak V, Richez C and Blanco P. in revision for Science Translational Medicine.

Plasmacytoid dendritic cells promote extrafollicular anti-DNA responses in lupus through type I interferon. Soni C, Perez o.A, Woss W.A, Serpas L, Mehl J, Goike J, Georgiou G, Ippolito G.C, Sisirak V* and Reizis B*. Immunity.2020,May 19:S1074-7613(20)30173-4. (*co-corresponding author)

Functions of Tfh Cells in Common Variable Immunodeficiency. Le Saos-Patrinos C, Loizon S, Blanco P, Viallard JF, Duluc D. Front Immunol. Jan 2020;11:6.

HIV protease inhibitors and autoimmunity: an odd, but promising idea. Galli G, Poissonnier A, Guégan J.P, Charrier M, Sisirak V, Lazaro E, Truchetet M.E, Richez C, Legembre P, Blanco P. Autoimmun Rev. 2019 Oct;18(10):102370.

Beyond the tumour microenvironment.Laplane L, Duluc D, Bikfalvi A, Larmonier N, Pradeu T. Int J Cancer. Nov 2019;145(10):2611-2618.

Dnase1l3 deletion causes aberrations in length and end-motif frequencies in plasma DNA. Serpas L, Chan RWY, Jiang P, Ni M, Sun K, Rashidfarrokhi A, Soni C, Sisirak V, Lee WS, Cheng SH, Peng W, Chan KCA, Chiu RWK, Reizis B, Lo YMD. Proc Natl Acad Sci U S A. 2019 Jan 8;116(2):641-649.

The Multiple Layers of the Tumor Environment. Laplane L, Duluc D, Larmonier N, Pradeu T, Bikfalvi A. Trends Cancer. Dec 2018;4(12):802-809.

Plasmacytoid dendritic cells are largely dispensable for the pathogenesis of experimental inflammatory bowel disease. Sawai C.M, Serpas L, Neto AG, Jang G, Rashidfarrokhi A, Kolbeck R, Sanjuan MA, Reizis B* and Sisirak V*, Front Immunol. 2018 Oct 25;9:2475. (*co-corresponding author)

Increase of follicular helper T cells skewed toward a Th1 profile in CVID patients with non-infectious clinical complications. Turpin D, Furudoi A, Parrens M, Blanco P, Viallard JF, Duluc D. Clin Immunol. 2018 Dec;197:130-138.

Innate Immunity in Systemic Sclerosis Fibrosis: Recent Advances. Laurent P*, Sisirak V*, Lazaro E, Richez C, Duffau P, Blanco P, Truchetet ME, Contin-Bordes C. Front Immunol. 2018 Jul 23;9:1702. Review. (*co-first author)

T Follicular Helper Cells in Autoimmune Disorders. Gensous N, Charrier M,Duluc D, Contin-Bordes C, Truchetet ME, Lazaro E, Duffau P, Blanco P, Richez C. Front Immunol. 2018Jul 17;9:1637.

Systemic lupus erythematosus and systemic sclerosis: All roads lead to platelets. Scherlinger M, Guillotin V, Truchetet ME, Contin-Bordes C, Sisirak V, Duffau P, Lazaro E, Richez C, Blanco P. Autoimmun Rev. 2018 Jun;17(6):625-635.

New Insights on Platelets and Platelet-Derived Microparticles in Systemic Lupus Erythematosus. Scherlinger M, Sisirak V, Richez C, Lazaro E, Duffau P, Blanco P. Curr Rheumatol Rep. 2017 Aug;19(8):48. Review.

The Antigen-Presenting Potential of Vγ9Vδ2 T Cells During Plasmodium falciparum Blood-Stage Infection. Howard J, Loizon S, Tyler CJ,Duluc D, Moser B, Mechain M, Duvignaud A, Malvy D, Troye-Blomberg M, Moreau JF, Eberl M, Mercereau-Puijalon O, Déchanet-Merville J, Behr C, Mamani-Matsuda M. J Infect Dis. 2017 May 15;215(10):1569-1579.

Dendritic cell targeting vaccine for HPV-associated cancer. Yin W, Duluc D, Joo H, Oh S. Cancer Cell Microenviron. 2016;3(4):e1482.

Therapeutic HPV Cancer Vaccine Targeted to CD40 Elicits Effective CD8+ T-cell Immunity. Yin W,Duluc D, Joo H, Xue Y, Gu C, Wang Z, Wang L, Ouedraogo R, Oxford L, Clark A, Parikh F, Kim-Schulze S, Thompson-Snipes L, Lee SY, Beauregard C, Woo JH, Zurawski S, Sikora AG, Zurawski G, Oh S. Cancer Immunol Res. 2016 Oct;4(10):823-834.

Digestion of Chromatin in Apoptotic Cell Microparticles Prevents Autoimmunity. Sisirak V*, Sally B*, D’Agati V, Martinez-Ortiz W, Özçakar ZB, David J, Rashidfarrokhi A, Yeste A, Panea C, Chida AS, Bogunovic M, Ivanov II, Quintana FJ, Sanz I, Elkon KB, Tekin M, Yalçınkaya F, Cardozo TJ, Clancy RM, Buyon JP, Reizis B. Cell. 2016 Jun 30;166(1):88-101. (*co-first author) Highlights: Onuora, S. DNASE1L3 prevents anti-DNA responses. Nat Rev Rheumatol 12, 437, 2016

A novel regulation of PD-1 ligands on mesenchymal stromal cells through MMP-mediated proteolytic cleavage. Dezutter-Dambuyant C, Durand I, Alberti L, Bendriss-Vermare N, Valladeau-Guilemond J, Duc A, Magron A, Morel AP, Sisirak V, Rodriguez C, Cox D, Olive D, Caux C. Oncoimmunology. 2015 Oct 29;5(3):e1091146.

Functional Specialty of CD40 and Dendritic Cell Surface Lectins for Exogenous Antigen Presentation to CD8(+) and CD4(+) T Cells. Yin W, Gorvel L, Zurawski S, Li D, Ni L,Duluc D, Upchurch K, Kim J, Gu C, Ouedraogo R, Wang Z, Xue Y, Joo H, Gorvel JP, Zurawski G, Oh S.EBioMedicine. 2016;5:46-58.

Plasmacytoid dendritic cells are dispensable for noninfectious intestinal IgA responses in vivo. Moro-Sibilot L, This S, Blanc P, Sanlaville A, Sisirak V, Bardel E, Boschetti G, Bendriss-Vermare N, Defrance T, Dubois B, Kaiserlian D. Eur J Immunol. 2016 Feb;46(2):354-9.

Protein Tyrosine Phosphatase PTPRS Is an Inhibitory Receptor on Human and Murine Plasmacytoid Dendritic Cells. Bunin A, Sisirak V, Ghosh HS, Grajkowska LT, Hou ZE, Miron M, Yang C, Ceribelli M, Uetani N, Chaperot L, Plumas J, Hendriks W, Tremblay ML, Häcker H, Staudt LM, Green PH, Bhagat G, Reizis B. Immunity. 2015 Aug 18;43(2):277-88.

 Transcriptional fingerprints of antigen-presenting cell subsets in the human vaginal mucosa and skin reflect tissue-specific immune microenvironments. Duluc D*, Banchereau R*, Gannevat J, Thompson-Snipes L, Blanck JP, Zurawski S, Zurawski G, Hong S, Rossello-Urgell J, Pascual V, Baldwin N, Stecher J, Carley M, Boreham M, Oh S. Genome Med. 2014;6(11):98. (*co-first author)

Chemoradiotherapy-induced upregulation of PD-1 antagonizes immunity to HPV-related oropharyngeal cancer. Parikh F,Duluc D, Imai N, Clark A, Misiukiewicz K, Bonomi M, Gupta V, Patsias A, Parides M, Demicco EG, Zhang DY, Kim-Schulze S, Kao J, Gnjatic S, Oh S, Posner MR, Sikora AG.Cancer Res. 2014;74(24):7205-7216.

C-type lectin-like receptor LOX-1 promotes dendritic cell-mediated class-switched B cell responses. Joo H, Li D, Dullaers M, Kim TW,Duluc D, Upchurch K, Xue Y, Zurawski S, Le Grand R, Liu YJ, Kuroda M, Zurawski G, Oh S. Immunity. 2014 Oct 16;41(4):592-604.

IL-26 is overexpressed in chronically HCV-infected patients and enhances TRAIL-mediated cytotoxicity and interferon production by human NK cells. Miot C*, Beaumont E*,Duluc D*, Le Guillou-Guillemette H, Preisser L, Garo E, Blanchard S, Hubert Fouchard I, Créminon C, Lamourette P, Fremaux I, Calès P, Lunel-Fabiani F, Boursier J, Braum O, Fickenscher H, Roingeard P, Delneste Y, Jeannin P. Gut. 2015;64(9):1466-1475. (*co-first author)

Genetic evidence for the role of plasmacytoid dendritic cells in systemic lupus erythematosus. Sisirak V*, Ganguly D*, Lewis KL, Couillault C, Tanaka L, Bolland S, D’Agati V, Elkon KB, Reizis B. J Exp Med. 2014 Sep 22;211(10):1969-76. (*co-first author). Highlights: Onuora, S. Depleting plasmacytoid dendritic cells: a new therapeutic approach in SLE?. Nat Rev Rheumatol 10, 573, 2014

Induction and activation of human Th17 by targeting antigens to dendritic cells via dectin-1.Duluc D, Joo H, Ni L, Yin W, Upchurch K, Li D, Xue Y, Klucar P, Zurawski S, Zurawski G, Oh S.J Immunol. 2014;192(12):5776-5788.

Transcription factor Runx2 controls the development and migration of plasmacytoid dendritic cells. Sawai CM, Sisirak V, Ghosh HS, Hou EZ, Ceribelli M, Staudt LM, Reizis B. J Exp Med. 2013 Oct 21;210(11):2151-9.

The role of dendritic cells in autoimmunity. Ganguly D, Haak S, Sisirak V, Reizis B. Nat Rev Immunol. 2013 Aug;13(8):566-77. Review.

ICOS is associated with poor prognosis in breast cancer as it promotes the amplification of immunosuppressive CD4+ T cells by plasmacytoid dendritic cells. Faget J, Sisirak V, Blay JY, Caux C, Bendriss-Vermare N, Ménétrier-Caux C. Oncoimmunology. 2013 Mar 1;2(3):e23185.

Tumor promotion by intratumoral plasmacytoid dendritic cells is reversed by TLR7 ligand treatment. Le Mercier I, Poujol D, Sanlaville A, Sisirak V, Gobert M, Durand I, Dubois B, Treilleux I, Marvel J, Vlach J, Blay JY, Bendriss Vermare N, Caux C, Puisieux I, Goutagny N. Cancer Res. 2013 Aug 1;73(15):4629-40.

Plasmacytoid dendritic cells deficient in IFNα production promote the amplification of FOXP3+ regulatory T cells and are associated with poor prognosis in breast cancer patients. Sisirak V, Faget J, Vey N, Blay JY, Ménétrier-Caux C, Caux C, Bendriss-Vermare N. Oncoimmunology. 2013 Jan 1;2(1):e22338.

Breast cancer-derived transforming growth factor-β and tumor necrosis factor-α compromise interferon-α production by tumor-associated plasmacytoid dendritic cells. Sisirak V, Vey N, Goutagny N, Renaudineau S, Malfroy M, Thys S, Treilleux I, Labidi-Galy SI, Bachelot T, Dezutter-Dambuyant C, Ménétrier-Caux C, Blay JY, Caux C, Bendriss-Vermare N. Int J Cancer. 2013 Aug 1;133(3):771-8.

Dendritic cells and vaccine design for sexually-transmitted diseasesDuluc D, Gannevat J, Joo H, Ni L, Upchurch K, Boreham M, Carley M, Stecher J, Zurawski G, Oh S.Microb Pathog. 2013;58:35-44.

Functional diversity of human vaginal APC subsets in directing T-cell responsesDuluc D, Gannevat J, Anguiano E, Zurawski S, Carley M, Boreham M, Stecher J, Dullaers M, Banchereau J, Oh S.Mucosal Immunol. 2013;6(3):626-638.

Impaired IFN-α production by plasmacytoid dendritic cells favors regulatory T-cell expansion that may contribute to breast cancer progression. Sisirak V*, Faget J*, Gobert M, Goutagny N, Vey N, Treilleux I, Renaudineau S, Poyet G, Labidi-Galy SI, Goddard-Leon S, Durand I, Le Mercier I, Bajard A, Bachelot T, Puisieux A, Puisieux I, Blay JY, Ménétrier-Caux C, Caux C, Bendriss-Vermare N. Cancer Res. 2012 Oct 15;72(20):5188-97. (*co-first author)

Targeting self- and foreign antigens to dendritic cells via DC-ASGPR generates IL-10-producing suppressive CD4+ T cells.Li D, Romain G, Flamar AL,Duluc D, Dullaers M, Li XH, Zurawski S, Bosquet N, Palucka AK, Le Grand R, O’Garra A, Zurawski G, Banchereau J, Oh S.J Exp Med. 2012;209(1):109-121.

Gene expression profiling identifies sST2 as an effector of ErbB2-driven breast carcinoma cell motility, associated with metastasis. Gillibert-Duplantier J, Duthey B, Sisirak V, Salaün D, Gargi T, Trédan O, Finetti P, Bertucci F, Birnbaum D, Bendriss-Vermare N, Badache A. Oncogene. 2012 Jul 26;31(30):3516-24.

CCR6/CCR10-mediated plasmacytoid dendritic cell recruitment to inflamed epithelia after instruction in lymphoid tissues. Sisirak V, Vey N, Vanbervliet B, Duhen T, Puisieux I, Homey B, Bowman EP, Trinchieri G, Dubois B, Kaiserlian D, Lira SA, Puisieux A, Blay JY, Caux C, Bendriss-Vermare N. Blood. 2011 Nov 10;118(19):5130-40.

Quantitative and functional alterations of plasmacytoid dendritic cells contribute to immune tolerance in ovarian cancer. Labidi-Galy SI, Sisirak V, Meeus P, Gobert M, Treilleux I, Bajard A, Combes JD, Faget J, Mithieux F, Cassignol A, Tredan O, Durand I, Ménétrier-Caux C, Caux C, Blay JY, Ray-Coquard I, Bendriss-Vermare N. Cancer Res. 2011 Aug 15;71(16):5423-34.

IL-6 and leukemia-inhibitory factor are involved in the generation of tumor-associated macrophage: regulation by IFN-γ.Jeannin P, Duluc D, Delneste Y. Immunotherapy. 2011;3(4 Suppl):23-26.

Plasmacytoid dendritic cells: recent progress and open questions. Reizis B, Bunin A, Ghosh HS, Lewis KL, Sisirak V. Annu Rev Immunol. 2011;29:163-83. Review.

Concomitant activation and antigen uptake via human dectin-1 results in potent antigen-specific CD8+ T cell responses.Ni L, Gayet I, Zurawski S,Duluc D, Flamar AL, Li XH, O’Bar A, Clayton S, Palucka AK, Zurawski G, Banchereau J, Oh S.J Immunol. 2010;185(6):3504-3513.

The IL-27 p28 subunit binds cytokine-like factor 1 to form a cytokine regulating NK and T cell activities requiring IL-6R for signaling. Crabé S, Guay-Giroux A, Tormo AJ,Duluc D, Lissilaa R, Guilhot F, Mavoungou-Bigouagou U, Lefouili F, Cognet I, Ferlin W, Elson G, Jeannin P, Gauchat JF. J Immunol. 2009;183(12):7692-7702.

PolyI:C plus IL-2 or IL-12 induce IFN-gamma production by human NK cells via autocrine IFN-beta. Duluc D, Tan F, Scotet M, Blanchard S, Frémaux I, Garo E, Horvat B, Eid P, Delneste Y, Jeannin P. Eur J Immunol. 2009 Oct;39(10):2877-84

Interferon-gamma reverses the immunosuppressive and protumoral properties and prevents the generation of human tumor-associated macrophages. Duluc D, Corvaisier M, Blanchard S, Catala L, Descamps P, Gamelin E, Ponsoda S, Delneste Y, Hebbar M, Jeannin P. Int J Cancer. 2009 Jul 15;125(2):367-73.

Tumor-associated leukemia inhibitory factor and IL-6 skew monocyte differentiation into tumor-associated macrophage-like cells. Duluc D, Delneste Y, Tan F, Moles MP, Grimaud L, Lenoir J, Preisser L, Anegon I, Catala L, Ifrah N, Descamps P, Gamelin E, Gascan H, Hebbar M, Jeannin P.Blood. 2007;110(13):4319-4330.

Human Langerhans cells express a specific TLR profile and differentially respond to viruses and Gram-positive bacteria. Flacher V, Bouschbacher M, Verronèse E, Massacrier C, Sisirak V, Berthier-Vergnes O, de Saint-Vis B, Caux C, Dezutter-Dambuyant C, Lebecque S, Valladeau J. J Immunol. 2006 Dec 1;177(11):7959-67.

Histamine and prostaglandin E up-regulate the production of Th2-attracting chemokines (CCL17 and CCL22) and down-regulate IFN-gamma-induced CXCL10 production by immature human dendritic cells. McIlroy A, Caron G, Blanchard S, Frémaux I,Duluc D, Delneste Y, Chevailler A, Jeannin P. Immunology. 2006;117(4):507-516.

Direct stimulation of human T cells via TLR5 and TLR7/8: flagellin and R-848 up-regulate proliferation and IFN-gamma production by memory CD4+ T cells. Caron G,Duluc D, Frémaux I, Jeannin P, David C, Gascan H, Delneste Y. J Immunol. 2005;175(3):1551-1557.

COLLABORATIONS

Dr. Alexandre Belot, CIRI, and Hospital of Lyon
Dr. Marc Dalod, CIML, Marseille
Dr. Olivier Adotevi, Université Franche Compté
Dr. Lucile Capuron, NeutriNeuro, Bordeaux
Dr. Patrick Blanco, Immunoconcept, Bordeaux
Dr. Thomas Pradeu, Immunoconcept, Bordeaux
Dr. Nathalie Schmittt, Immunoconcept, Bordeaux
Dr. Edouard Forcade, Immunoconcept, Bordeaux
Dr. Maria Mamani Matsuda, Immunoconcept, Bordeaux

Dr. Boris Reisiz, New York University, New York, USA
Dr. Dipyaman Ganguly, CSIR, Kolkata, India

FUNDING