Abstract
BACKGROUND: Antibody alone cannot provide optimal protection against many infectious diseases impacting global heath. In these cases, our challenge is to develop innovative vaccines that generate protective populations of memory T cells. However, our studies suggest that current paradigms explaining how memory CD4 T cells provide protection are inadequate. This is likely due to both the paucity of and heterogeneity of memory CD4 T cells observed in vivo, which make analysis extremely difficult. SUMMARY: Here, we discuss new findings that indicate there is extensive functional heterogeneity within effector and memory CD4 T cell populations both in vivo and in vitro. Using influenza as an example, we also discuss the merits of employing reductionist approaches to explore how unique subsets of CD4 T cells are generated, what mechanisms of protection they use, and where they stand on the axes of differentiation that define T cell subsets.