Immune Regulation and Vaccinology - INSERM U883  


  HEADPr LECLERC Claude / cleclerc@pasteur.fr
  MEMBERSDr. ALIGNANI Diego / Dr DADAGLIO Gilles / DEMOND Anne / DERIAUD Edith / Dr. FAYOLLE Catherine / DONG Hui / JARON Barbara / LE PAGE Aurélie / 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 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 presentation of exogenous antigens to CD8+ T cells (cross-presentation) by pDCs are under investigation. Furthermore, we are deciphering the role of pDC in the induction of tumor immunity using a mouse model lacking pDC recently developed by our group.

Regulation of neonatal dendritic cell functions. We are investigating the innate and adaptive regulatory mechanisms responsible for the high susceptibility to infections and poor responses to vaccines observed in newborns. We evidenced a crosstalk between neonatal Bregs cells and DC, following TLR activation, leading to impaired pro-inflammatory 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. We are currently investigating TLR-independent innate pathways that activate neonatal DC, but not Bregs, for efficient priming of Th1 and Th17 responses.

Anti-mycobacterial immunity. We demonstrated that, subsequent to vaccination with Mycobacterium bovis BCG (Bacillus Calmette-Guérin), regulatory T cells (Treg) are recruited to the draining lymph nodes and negatively control anti-mycobacterial Th1 cell responses against subdominant and immunodominant regions of mycobacterial antigens. Concomitantly, attenuation of Treg subset, has a significantly positive impact on the protective capacity of BCG against pulmonary infection with M. tuberculosis. Thus, for rational design of improved anti-tuberculosis vaccine, factors able to inhibit Treg development, like cytokines, have to be considered.

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

Riv.jpg

Antigen-presenting cells internalizing ovalbumin before degradation and presentation



  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

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 dendritric 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





Activity Reports 2009 - Institut Pasteur
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