Immune Regulation and Vaccinology - INSERM U883  


  HEADPr LECLERC Claude / cleclerc@pasteur.fr
  MEMBERSDr. ALIGNANI Diego / Dr. ARRIBILLAGA ARANGOA Laura / BENECHET Alexandre / Dr DADAGLIO Gilles
DEMOND Anne / DERIAUD Edith / Dr. FAYOLLE Catherine / Dr OLIVIER Aurélie / JARON Barbara
Dr LO-MAN Richard / Dr MAJLESSI Laleh / MOURIES Juliette / ROJAS Marie / Dr. SAINZ PEREZ Alexander
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 a therapeutic vaccine candidate against cervical cancer. Administration of this vaccine with CpG and low-dose 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 clinicals trials are being organized to test these therapeutic vaccine candidates.

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 showed that pDC induced antigen-specific effector/memory T cells after viral stimulation. Our results also established that pDC capture and cross-present soluble or particulate antigens in vivo following stimulation by TLR7 or TLR9 ligands leading to cross-priming of naive CD8+ T cells. Thus, pDC can play a role in both innate and adaptive anti-viral immunity.

Ontogeny, functions and regulation of neonatal dendritic cells. We are investigating the contribution of DC to the high susceptibility to infections and to biased Th2 responses observed in newborns. We found that neonatal DC are fully functional for innate responses and in their capacity to prime Th1 responses. However, following TLR triggering in vivo, a crosstalk between neonatal B cells and DC is engaged leading to restricted proinflammatory and Th1 responses. This regulatory mechanism involves CD5+ B cells, is dependent on both IL-10 and type I IFNs, and likely contributes to neonatal susceptibility to infections.

Mycobacterial antigen presentation. Mycobacteria escape host innate immune responses by surviving in phagosomes of host antigen-presenting cells (APC) and by blocking their delivery to lysosomes. This phenomenon may be involved in modulation of MHC class I-/II-dependent T cell responses. We showed that presentation of mycobacterial Ags and induction of CD4+ or CD8+ CTL responses are independent of the site of intracellular residence in APC. Thus, the limiting factor for the generation of immune responses against mycobacteria is not the degree of lysosomal delivery, which has to be considered in the rational design of anti-mycobacterial vaccines.

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



  Publications

Sun CM, Deriaud E, Leclerc C, Lo-Man R. (2005) Upon TLR9 signaling, CD5+ B cells control the IL-12-dependent Th1-priming capacity of neonatal DCs. Immunity, 22:467-77.PMID: 15845451

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

Hervas-Stubbs S, Olivier A, Boisgerault F, Thieblemont N, Leclerc C. (2007) . TLR3 ligand stimulates fully functional memory CD8+ T cells in the absence of CD4+ T-cell help. Blood, 109:5318-26.PMID: 17339421

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

Majlessi L, Combaluzier B, Albrecht I, Garcia JE, Nouze C, Pieters J, Leclerc C. (2007). Inhibition of phagosome maturation by mycobacteria does not interfere with presentation of mycobacterial antigens by MHC molecules.J Immunol., 179:1825-33. Erratum in: J Immunol. 2007 179:5604.PMID: 17641049





Activity Reports 2007 - Institut Pasteur
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