Generation, persistence and plasticity of CD4 T‐cell memories

<jats:title>Summary</jats:title><jats:p>The development of immune memory mediated by T lymphocytes is central to durable, long‐lasting protective immunity. A key issue in the field is how to direct the generation and persistence of memory T cells to elicit the appropriate secondary response to provide protection to a specific pathogen. Two prevailing views have emerged; that cellular and molecular regulators control the lineage fate and functional capacities of memory T cells early after priming, or alternatively, that populations of memory T cells are inherently plastic and subject to alterations in function and/or survival at many stages during their long‐term maintenance. Here, we will review current findings in CD4 T‐cell memory that suggest inherent plasticity in populations of memory CD4 T cells at all stages of their development – originating with their generation from multiple types of primed CD4 T cells, during their persistence and homeostatic turnover in response to T‐cell receptor signals, and also following secondary challenge. These multiple aspects of memory CD4 T‐cell flexibility contrast the more defined lineages and functions ascribed to memory CD8 T cells, suggesting a dynamic nature to memory CD4 T‐cell populations and responses. The flexible attributes of CD4 T‐cell memory suggest opportunities and mechanisms for therapeutic manipulation at all phases of immune memory development, maintenance and recall.</jats:p>