Generation, persistence and plasticity of CD4 T-cell memories

Abstract

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.

Figure 1

Multiple precursors generate memory CD4 T cells. The model depicts CD4 T-cell differentiation following antigen activation of naive CD4 T cells with increased effector capacity of the population following increased antigen stimulation. The end stage of T-cell differentiation is maximal differentiation to effector cells which ultimately die. At multiple stages before reaching the activation threshold for effector cell death, activated CD4 T cells at distinct differentiation states can branch off to develop and persist as memory CD4 T cells. DC, dendritic cell; MHC, major histocompatibility complex; TCR, T-cell receptor.

Figure 2

Model for memory CD4 T-cell plasticity in secondary responses. Schematic diagram of possible mechanisms for flexibility in recall responses by a population of antigen-specific memory CD4 T cells, because of direct antigenic recall (centre arrows), or via altered persistence because of homeostatic mechanisms (top and bottom arrows). For explanation, see text.