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.

Visualizing the initial stages of T cell activation

Previous studies have proposed that transient contacts between T cells and dendritic cells (DCs) precede the formation of long-lived interactions. We have recently developed a new experimental approach to quantify and visualize the onset of T cell activation in vivo. Using intravital two photon imaging (Fig. 1), we found that the first encounter between antigen-bearing DCs and cognate CD4 T cells most often resulted in the formation of a long-lived interaction. This system is further used to dissect the requirement for T cell stop.

T cell competition during immune responses

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.

Cellular dynamics during CD4 T cell help

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 have identified 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.