|Dynamics of Immune Responses - Inserm Equipe Avenir U668|
|HEAD||BOUSSO Philippe / firstname.lastname@example.org|
|MEMBERS||Dr AZAR Georges / Dr BREART Beatrice / Dr CELLI Susanna / Dr. FILIPE-SANTOS Orchidée / LEMAÎTRE Fabrice / DEGUINE Jacques / BEUNEU Hélène/ HUGOT Bérengère
The orchestration of an adaptive immune response relies on a succession of dynamic molecular and cellular events taking place in specialized micro-environments. The outcome of T cell responses is influenced by contact-dependent information exchanges between various cell subsets, including CD4 and CD8 T lymphocytes, antigen-presenting cells and regulatory T cells. In the laboratory, we are studying how T cell responses are regulated by cell migration and by cell-cell interactions in lymph nodes. A combination of intravital two photon imaging with detailed functional studies is used to dissect T cell activation and function in vivo.
T cell competition during immune responses
We have explored the cellular basis for intraclonal competition. We found that while prolonged interactions between activated T cells and Ag-bearing DCs were infrequent at high T cell precursor frequency, they were readily observed for a period of at least 2 days when lower numbers of T cells were used. In fact, when present in high numbers, Ag-specific T cells were competing for the limited number of sites on DCs with sufficient peptide-MHC (pMHC) complexes for the establishment of a long-lived interaction. Thus, the period during which CD4 T cells continue to establish stable interactions is dictated both by Ag levels and T cell numbers, providing a feed-back mechanism for the termination of CD4 T cell responses.
Manipulation of T cell-DC contacts in vivo
T cells interact with dendritic cells (DCs) for periods lasting from minutes to hours. Yet, a causal link between the duration of this interaction and the efficiency of T cell activation has not been established in vivo. Employing intravital two photon imaging, we manipulated T cell-DC interactions in real-time and found that the first T cell-DC encounter often resulted in a long-lived interaction (Fig.1). Moreover, cessation of TCR-MHC signals promoted cellular dissociation suggesting that antigen availability on DCs regulates contact duration. Finally, at least 6 h of in vivo T cell-DC interaction were required for CD4+ T cells to undergo clonal expansion. These results establish the importance of prolonged T cell-DC interactions for efficient CD4+ T cell activation in vivo.
Imaging intratumoral CTL killing in solid tumors
Cytotoxic T lymphocytes (CTLs) have the potential to attack tumors and adoptive transfer of CTLs can lead to tumor regression in mouse models and human clinical settings. However, the dynamics of tumor cell elimination during efficient T cell therapy is unknown. To address these questions, we are performing real-time imaging of tumor cell apoptosis in vivo using intravital two-photon microscopy and a FRET-based reporter of caspase 3 activity. Using this approach, we are characterizing the spatiotemporal dynamics of intratumoral CTL killing in vivo in a mouse model of solid tumor.
Keywords: T cell activation, dendritic cell, imaging, tumor immunity
Celli, S., F. Lemaitre, and P. Bousso. 2007. Real-time manipulation of T cell-dendritic cell interactions in vivo reveals the importance of prolonged contacts for CD4+ T cell activation. Immunity 27:625
Garcia, Z., E. Pradelli, S. Celli, H. Beuneu, A. Simon, and P. Bousso. 2007. Competition for antigen determines the stability of T cell-dendritic cell interactions during clonal expansion. Proc Natl Acad Sci U S A 104:4553
Breart, B and P. Bousso. 2006. Cellular orchestration of T cell priming in lymph nodes. Curr Opin Immunol, 18:483
Beuneu. H, Garcia, Z and P. Bousso. 2006. Cognate CD4 help promotes recruitment of antigen-specific CD8 T cells around dendritic cells, J.Immunol., 177:1406
Celli, S, Garcia Z and P. Bousso. 2005 CD4 T cells integrate signals during successive DC encounters in vivo. J. Exp. Med, 202:1271.
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