Helpless CD8 T cell memory explained: prolonged antigen presentation drives a temporal rather than terminal defect

Abstract CD4 T cell help is critical for long-term antiviral CD8 T cell immunity. Despite seemingly normal effector properties, “helpless” CD8 memory T cells (TM) generated in the absence of CD4 T cells during initial priming exhibit a substantially blunted recall response. Yet, how lack of CD4 help specifically impairs CD8 TM formation in the context of acute viral infections remains elusive. Here, we demonstrate that in transiently and constitutively CD4 T cell-deficient mice “helpless” antiviral CD8 TM to acute lymphocytic choriomeningitis virus (LCMV) exhibit a wide array of homeostatic, phenotypic, and functional defects that are broadly consistent with delayed CD8 TM maturation. Mechanistically, “helpless” CD8 T cell memory is not grounded in altered CD8 effector T (TE) cell differentiation in the absence of CD4 T cells but in exposure of post-effector CD8 T cells to protracted viral antigen presentation. Conversely, efficient generation of “helped” CD8 T cell memory is contingent on CD40L-mediated activities by LCMV-specific CD4 T cells that promote timely clearance of viral antigen. Importantly, we show that “helpless” memory-precursor CD8 TE display comparable memory potential to their “helped” counterparts, and that, once viral antigen is cleared, complete resolution of “helpless” CD8 memory is achieved over a period of ~1.5 years during which “helpless” CD8 TM eventually acquire mature TM properties including fully restored recall capacities. Collectively, our data redefine “helpless” CD8 T cell memory as a temporal rather than terminal defect, with implications for our general conceptualization of CD8 T cell memory as well as for the development of preventive and therapeutic strategies to improve protective CD8 TM function. Supported by grant NIH R01AI093637.