Absolute Levels of ZAP70 Kinase Influence Maturation and Functional Responses of Peripheral T Cells 4451

Abstract Description T cell activation relies on phosphorylation of receptor-proximal kinases to transduce signals for gene expression and functional responses. Zeta-associated protein kinase 70 (ZAP70) is one of the earliest kinases activated after T cell receptor (TCR) engagement to fine tune distal signaling. While the significance of subsequent ZAP70 kinase activity in efficient TCR signaling is well characterized, how the absolute level of this protein itself modifies a T cell response is yet to be explored. Using a class-II restricted TCR transgenic model, we find that lowering the amount of total ZAP70 protein in thymocytes by just 2-fold using a heterozygous ZAP+/- background resulted in an ∼10-fold decrease in CD4+ Single Positives (SP) generation. This was accompanied by up to a 20-fold elevation in CD8+ SPs which persist in the periphery. Interestingly, even in ZAP-sufficient TCR transgenic mice, acute activation of T cells in vivo led to a 2-fold increase in total ZAP70 protein. Elevation in intracellular ZAP, correlating with efficient memory T cell responsiveness, has previously been described. Using an in vivo tolerance model for chronic stimulation of peripheral T cells rendering them poorly responsive to antigen, we find a further increase in total ZAP70 protein by about 5-fold. Given the surprising range of ZAP70 levels across distinct stages of T cell maturation, we use an inducible system as a comprehensive model for understanding how ZAP70 levels regulate T cell function. Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)