Immune Regulation and Vaccinology - INSERM U883  


  HEADPr LECLERC Claude / claude.leclerc@pasteur.fr
  MEMBERSDr DADAGLIO Gilles / DEMOND Anne / DERIAUD Edith / Dr. FAYOLLE Catherine / DONG Hui / GUILLEREY Camille / JARON Barbara / LE PAGE Aurélie / LOFANO Giuseppe / Dr LO-MAN Richard / Dr MAJLESSI Laleh / MOURIES Juliette / ROJAS Marie / Dr. SAINZ PEREZ Alexander / SAYES Fadel / SUN Lin / Dr SUN Cheng Ming / Dr. ZHANG Xiaoming


  Annual Report

The activity of our laboratory is focused on the understanding of the mechanisms that control the activation and regulation of T cell responses and on the development of new strategies of vaccination against tumors and infections.

Development of therapeutic anti-cancer vaccines. Based on the capacity of the adenylate cyclase (CyaA) to bind to dendritic cells (DC), we have developed a highly efficient vector capable of targeting a wide range of antigens to antigen presenting cells, leading to strong immune responses. We used this new vector to develop therapeutic vaccine candidates against cervical cancer and melanoma. Administration of CyaA vaccine with CpG and low-dose of cyclophosphamide completely overcame tumor-associated immunosuppression and eradicated large, established tumors in mice. We have also developed a second category of anti-cancer therapeutic vaccines, the MAG-Tn3, based on the synthesis of glycopeptides carrying the Tn carbohydrate tumor antigen. Several clinical trials are being organized to test these therapeutic vaccine candidates. In parallel, we are also analyzing the interaction between tumor cells and the immune system and in particular the development of regulatory mechanisms during tumor growth, such as myeloid suppressor cells and regulatory T lymphocytes.

Analysis of T cell responses induced by dendritic cell subpopulations. Plasmacytoid DC (pDC) are characterized by their high capacity to produce type I IFNs after stimulation. We demonstrated that pDC are able to induce antigen-specific effector/memory CD8+ T cells against both endogenous and exogenous antigens after activation. These results suggest that pDC can play a role in both innate and adaptive immunity. The mechanisms of induction of presentation of exogenous antigens to CD8+ T cells (cross-presentation) by pDC are under investigation. Furthermore, we developed a mouse model lacking pDC to characterize their functions in vivo. We are using this model to decipher the role of pDC in the induction and/or control of tumor immunity.

Immune regulation and design of efficient vaccines in neonates. Understanding the innate and adaptive regulatory mechanisms responsible for the high susceptibility to infections in newborns will help to improve vaccine design. We found a crosstalk between neonatal Bregs cells and DC, following TLR activation, leading to impaired pro-inflammatory and Th1 responses. We also identified a regulatory role of neutrophils in the context of bacterial infection following co-activation of TLR and C-type lectin/Syk pathways. We are currently investigating innate activation pathways that activate neonatal DC and bypass regulatory mechanisms to allow efficient priming of protective Th1/Th17 responses.

Anti-mycobacterial immunity. The live attenuated vaccine Mycobacterim bovis BCG (Bacillus Calmette-Guérin) is not able to protect efficiently against M. tuberculosis infection in the adult pulmonary tuberculosis. We developed an innovative strategy for the rational design of a new anti-mycobacterial vaccine by in vivo targeting of prominent mycobacterial antigens, i.e., proteins from ESX family, through a versatile approach, to diverse DC surface receptors, for instance integrins or C-type lectins, of diverse DC subsets with specialized functions. The latter will be able to control the induction and differentiation of T-cell responses with protective potential against M. tuberculosis infection.

Keywords: Vaccines, neonate, CTL, dendritic cells, cancer, T cells, immunotherapy, anti-mycobacterial immunity

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Antigen-presenting cells internalizing ovalbumin before degradation and presentation



  Publications

Zhang X, Deriaud E, Jiao X, Braun D, Leclerc C, Lo-Man R. (2007). Type I interferons protect neonates from acute inflammation through interleukin 10-producing B cells. J Exp Med., 204:1107-18.. PMID: 17485512

Berraondo P, Nouzé C, Préville X, Ladant D, Leclerc C. (2007). Eradication of large tumors in mice by a tritherapy targeting the innate, adaptive, and regulatory components of the immune system. Cancer Res. 67:8847-55.PMID: 17875726

J. Mouries, G. Moron, G. Schlecht, N. Escriou, G. Dadaglio and C. Leclerc. (2008). Plasmacytoid dendritic cells efficiently cross-prime naive T cells in vivo after TLR activation. Blood, 112: 3713-3722 . PMID: 18698004

B. Jaron, E. Maranghi, C. Leclerc and L. Majlessi. (2008). Effect of attenuation of Treg during BCG immunization on anti-mycobacterial Th1 responses and protection against Mycobacterium tuberculosis. PLoS One, 3, e2833. PMID: 18665224

X. Zhang, L. Majlessi, E. Deriaud, C. Leclerc and R. Lo-Man. (2009). Coactivation of Syk kinase and MyD88 adaptor protein pathways by bacteria promotes regulatory properties of neutrophils. Immunity, 31:761-71. PMID: 19913447





Activity Reports 2009 - Institut Pasteur
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