Unit: Dynamics of Immune Responses

Director: Philippe Bousso

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. Recent advances in imaging technology provide us with the opportunity to improve our understanding of immunity in physiological settings with high spatiotemporal resolution. The research of our lab aim at understanding how T cell responses are regulated by cell-cell interactions in the lymph nodes by combining intravital two photon imaging with detailed functional studies.

Naïve T lymphocytes home and traffic in particular area of the lymph nodes where they can encounter antigen (Ag)-bearing DC migrating from tissues. Depending on the immunological context, interactions between Ag-bearing DC and Ag specific T cell can result in either an effective or an abortive Ag-specific T cell response. Numerous parameters are known to modulate the outcome of T cell responses. Among these is the strength of signal delivered to the T cells which is influenced by the amount of Ag and costimulation on the DC surface and the duration of signaling. How the duration and frequency of T cell-DC contacts are regulated in vivo and how T cell differentiation is influenced by the dynamics of these contacts remain to be determined. In addition the outcome T cell response integrates contact-dependent information exchanges between multiple cell populations including responder CD4 and CD8 T cells, DC and regulatory T cells. For example, the generation of primary cytotoxic T cell responses against viruses and tumors and that of a functional pool of memory CD8 T cells can be critically dependent on the presence of CD4 T cells. However, the mechanism by which CD4 T cells provide help to CD8 T cell responses is still a matter of debate. Another important component of the regulation of the T cell response involved the action of a particular subset of T lymphocytes called regulatory T cells (Treg). CD4+CD25+ Treg can suppress CD4 and CD8 T cell responses in vitro and in vivo, but their mode of action in vivo is unclear. Dissecting the regulation of immune cellular interactions in the lymph node should provide new insights on how CD4 and CD8 T cells, DC and regulatory T cells act together to influence the outcome of T cell responses. Yet, most of our knowledge of how immune cells interact with each other comes either from in vitro cultures or snapshot images of in vivo experiments. These studies have provided an essential foundation for understanding the cellular responses to different stimuli. However, our ability to understand and manipulate the immune system in vivo has been limited in part by the technical difficulty to dissect the most dynamic aspects of the immune response in its native microenvironment. Recent advances in imaging technology provide us with the opportunity to improve our understanding of immunity in physiological settings with high spatiotemporal resolution. Over the last two years, we and others have shown that two photon laser scanning microscopy is a technique of choice to track in real-time fluorescently labeled immune cells in intact lymphoid organs. The initial application of this approach to the study of lymphoid tissues has provided a dramatic glimpse into how cells of the immune system move and interact in their native environment. By combining functional studies and dynamic imaging experiments, we aim at understanding how T cell responses are regulated by cell-cell interactions in vivo.

Tracking the history of CD4 T cell-DC interactions (Susanna Celli, Zacarias Garcia)

The cellular mode of T cell priming in vivo remains to be fully characterized. We have investigated the fate of T cell-DC interactions in the late phase of T cell activation in the lymph node. We found that, in general, CD4 T cells detach from DC prior to undergoing cell division.Using a new approach to track the history of antigen recognition events, we demonstrated that activated/divided T cells re-engage different DC in an antigen-specific manner. Two photonimaging of intact lymph nodes suggested that T cells can establish prolonged interactions with DC at multiple stages during the activation process. Importantly, signals delivered duringsubsequent DC contacts are integrated by the T cell and promote sustained IL-2Ra expression and IFN-g production. Thus, repeated encounters with Ag-bearing DC can occur in vivo andmodulate CD4 T cell differentiation programs.

Cellular dynamics during CD4 T cell help (Hélène Beuneu, Zacarias Garcia)

In many instances, CD4 helper T cells promote the quality of CD8 T cell responses, a phenomenon referred to as CD4 help. The cellular orchestration underlying CD4 help is not fully understood. We documented that the formation of three-cell clusters occurred as soon as day 1 and relied on long-lasting CD4 T cell-DC and CD8 T cell-DC interactions. We found that the influence of CD4 help on CD8 T cell differentiation could be observed as early as the second round of cell division. Importantly, our results identify a new facet to the phenomenon of CD4 help in which DCs, upon cognate interactions with CD4 T cells, increase their ability to attract/retain Ag-specific CD8 T cells. Our results support a model in which CD4 help operates rapidly, in part by favoring CD8 T cells recruitment around those DCs that are the most competent for priming.

Keywords: T cell, dendritic cells, activation, imaging, cell interactions

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