The role of CD28-mediated signals in programming and reprogramming of mouse and human memory and induced regulatory T cells

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Upon appropriate stimulation, naive T cells express certain transcription factors such as T-bet or Gata-3 which guide their differentiation into functionally polarised complementary effector/memory populations. These cells belonging to the Th1, Th2 or to the more recently identified Th17 lineages are then thought to cross-regulate each other. However, there is now a substantial body of evidence for lineage plasticity meaning that e.g. Th2 cells may also acquire properties of Th1 cells. While the role of CD28-mediated co-stimulation is well documented during primary differentiation of naive T cells into effector/memory cells, the impact of CD28 stimulation on the reprogramming of effector and memory T cells is so far largely unknown. Moreover, induced Foxp3+ regulatory T cells, which bear great therapeutic potential, also display a high degree of plasticity in vivo depending on the disease model studied. In the experiments proposed herein we would, therefore, like to address the impact of CD28 stimulation on the reprogramming of fully differentiated mouse and human T cells in greater detail. To this end we will not only use CD28-specific reagents blocking ligand binding but also the novel inducible CD28-deleter mouse strain CD28-/flox, rosa(CreERT2) (iCD28k.o.) to study T cell reprogramming in vitro and during antigen-driven immune responses in vivo. We believe that the scheduled experiments will not only provide deeper insights into T cell differentiation in general but will also help to develop novel therapeutic strategies for humans who, in contrast to cleanly housed laboratory mice, contain large populations of fully differentiated memory T cells.