Varying pMHC-TCR affinity at the memory checkpoint alters the number and phenotype of memory CD4 T cells.

Abstract

Abstract We have defined a memory checkpoint, 5–7 days post infection (dpi) with influenza A virus (IAV), during which responding CD4 effector cells need to re-encounter their cognate antigen (Ag) to effectively transition to memory. Ag encounter during this checkpoint promotes CD4 effector and memory survival, cytokine production potential, and leads to enhanced protection against lethal IAV challenge. Activated APC, pulsed with peptide, are sufficient to drive effectors to memory in vivo. Therefore, we can determine what influence Ag dose and affinity, at the effector stage, have on memory generation. We have developed an IAV-specific TCR transgenic mouse with CD4 T cells specific for an immunodominant, highly conserved, influenza nucleoprotein determinant (NP311–325). Using several altered peptide ligands with varying affinities that activate the transgenic CD4 T cells to varying degrees, we can analyze how varying pMHC-TCR affinity at the memory checkpoint influences the generation of the CD4 memory population. Our preliminary data indicate that when CD4 T cells encounter high, as compared to the medium and low affinity peptides during the memory checkpoint, they more efficiently develop into memory cells. If high affinity and/or dose of peptide is needed, it would imply continuing infection at the checkpoint is optimum for generating CD4 memory and should inform the kind of vaccine strategies that can successfully mimic live infection.