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In vivo characterisation of Follicular Helper T cells (TFHcells)
Start date: Jun 1, 2010, End date: May 31, 2014 PROJECT  FINISHED 

An effective immune response relies on the helper T cell (TH) regulated development of high-affinity B cell memory. Follicular Helper T (TFH) cells are the critical regulators of the B cell response. Until recently, TFH cells were considered fully differentiated cells prone to apoptosis. However, we showed that protein vaccination selects locally effector TFH cells that become memory TFH cells and that remain in draining lymphoid tissue. Long-term cellular depots of antigen in the form of peptide-MHC complexes (pMHCII) and continued expression of the C-type lectin CD69 provide a mechanism for retaining TFH cells. Much is still to be learnt about the phenotype, function and ultimate fate of TFH cells. The relationship of effector TFH cells to other effector TH cell subsets and the mechanisms that control TFH cell differentiation are still uncovered. The genetic program imprinted in TFH cells by unique transcription factor(s), the role of cytokines or co-stimulatory signals and the impact of the inflammatory context in vivo in controlling TFH differentation will be assessed in the specific aim 1. Furthermore, unraveling the development and appropriate placement of memory TFH cells becomes an important issue. In specific aim 2, we will clarify the mechanism and role of memory TFH cell retention locally. First, we will assess the role of pMHCII depot by identifying which Antigen Presenting Cells (APC) express these depots. Next, we will confirm the importance of those APC in mice rendered deficient for this distinct population and test its physiological role. Finally, we will examine the role of CD69 as a potential retention mechanism in CD69-deficient mice. Over the course of these studies we will provide fundamental new insights into the mechanisms controlling adaptive immunity and help to define the best means to obtain long-lasting high-affinity B cell immunity to protein antigens with potentially high impact on the public health initiative of vaccine design.

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