Prolonged antigen presentation in absence of CD4 T cells promotes reversible defects of helpless CD8 memory T cells across multiple host-pathogen systems 4320

Abstract Description Generation of functional CD8 T cell memory typically requires engagement of CD4 T cells. However, in certain scenarios, such as acutely-resolving infections, effector (TE) and subsequent memory (TM) CD8 T cell formation may appear impervious to a lack of CD4 T cell help during priming. Yet, such helpless CD8 TM respond poorly to pathogen rechallenge. At present, the origin and long-term evolution of helpless CD8 T cell memory remain poorly understood. Using the lymphocytic choriomeningitis virus (LCMV), influenza virus (IAV), vaccinia virus (VV), and Listeria monocytogenes (LM) systems, we demonstrate that CD8 TE differentiation under helpless conditions paradoxically favors the accumulation of TCF1hi central memory precursors, but exposure of post-effector CD8 T cells to lingering antigen in the absence of infectious pathogens interferes with the evolution of the developing CD8 TM pool. While extended “de-differentiation” of CD8 TEM to TCM eventually supports full maturation including restored TM recall capacity in LCMV, helpless IAV-, VV- and LM-specific CD8 TM undergo accelerated remodeling with an early loss of terminal TEM and concomitant enrichment of highly functional TCM subsets. Notwithstanding model-specific differences (e.g., dosage/route of infection, epitope hierarchies), our data highlight a shared essential role for prolonged antigen presentation in shaping CD8 T cell memory and emphasize striking CD8 TM plasticity with implications for vaccination strategies. Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)