VISUALIZING IMMUNITY · Dynamics of T cell activation and anti-tumor T cell activity in vivo

Final Activity Report Summary - VISUALISING IMMUNITY (Dynamics of T cell activation and anti-tumour T cell activity in vivo)

Our project aimed at identifying novel cellular mechanisms contributing to the shaping of T cell responses in vivo. To this end, we proposed to take advantage of intravital two-photon imaging to decode the cellular dynamics underlying T cell activation in secondary lymphoid organs and T cell effector activity in peripheral tissues. Lymph nodes are sites where naïve T cells in search of their cognate antigen have the opportunity to survey dendritic cells (DCs), the most potent antigen-presenting cells (APCs), for their activation. The establishment of a cellular contact between a T cell and a DC provides the opportunity for antigen recognition through T-cell receptor (TCR) interactions with peptide-MHC complexes present at the DC surface. Despite our fundamental understanding of T-cell activation, how individual T cells experience their encounters with DCs in vivo has remained largely unknown. A naive T cell spends an average of 24 hr in a given lymph node but this duration is extended to 3-4 days when it is exposed to its cognate antigen. What precisely happens during this period has long been considered a black box, as many fundamental questions remain unanswered. An important part of the efforts of my EXTgroup aimed at addressing the following questions: i) What are the mechanisms that favour productive T-cell-DC encounters? ii) How is the sequence of cellular events that leads to T-cell activation regulated and iii) How do T cells collect and integrate signals during their interactions with DCs? To address these fundamental questions, we have been utilising two-photon imaging to shed light on cell-cell interactions and the mechanism of immune activation. Our results have contributed to a deeper understanding of how the orchestrated 'conversation' between T cells and DCs shapes the magnitude, quality and heterogeneity of adaptive immune response. After being primed in secondary lymphoid organs, antigen-specific CD4 and CD8 T cells migrate to peripheral tissues where antigen recognition triggers their effector functions such as cytotoxicity or cytokine/chemokine production. The second aim of our research is to understand how specific microenvironments impact on the migration, interaction and activity of effector T cells. Of particular interest is the role of the tumour microenvironment and that associated with chronic infection. Over the last years, we have started to established model systems in which we can study effector T cell in the context of disease pathogenesis.

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