A checkpoint requiring cognate antigen recognition at the effector stage is necessary for protective memory CD4 T cell generation.

Abstract

Abstract Effective vaccination depends on the generation of memory T cells, B cells, and long-lived plasma cells. However, the mechanisms that govern memory CD4 T cell formation are not well understood. Antigen (Ag) recognition during priming drives effector generation, but it is unclear how Ag recognition at the effector stage impacts T cell fate. Using an influenza infection model, we find that effector CD4 T cells must re-encounter Ag at the effector phase to avoid default apoptosis and become memory. Cognate interaction at this defined “memory checkpoint” drives continued proliferation, enhances survival, upregulates memory markers CD25, CD127, CXCR3, and Bcl-6, and drives IL-2 production, resulting in the formation of long-lived memory cells with enhanced production of multiple cytokines and increased protective function. A cold-adapted influenza virus, like those used in live-attenuated influenza vaccines, fails to present Ag at this critical effector time point and fails to induce substantial CD4 memory. However, memory CD4 T cell formation was rescued by adding short-lived Ag-pulsed antigen presenting cells during the checkpoint. Importantly, the Ag alone without infection-induced inflammation, was sufficient to restore memory formation. Our findings imply that in order for vaccines to promote optimal memory CD4 T cell formation, they must provide Ag presentation long enough that effector CD4 T cells are effectively restimulated during the “memory checkpoint”.