CD4 T-cell memory generation and maintenance

Abstract

Immunologic memory is the adaptive immune system's powerful ability to remember a previous antigen encounter and react with accelerated vigor upon antigen re-exposure. It provides durable protection against reinfection with pathogens and is the foundation for vaccine-induced immunity. Unlike the relatively restricted immunologic purview of memory B cells and CD8 T cells, the field of CD4 T-cell memory must account for multiple distinct lineages with diverse effector functions, the issue of lineage commitment and plasticity, and the variable distribution of memory cells within each lineage. Here, we discuss the evidence for lineage-specific CD4 T-cell memory and summarize the known factors contributing to memory-cell generation, plasticity, and long-term maintenance.

FIG. 1. An integrated model of CD4 T-cell memory differentiation

TH1: Exposure of CD4 T cells to IL-12 and IL-2 leads to T-bet up-regulation and subsequent TH1 cell differentiation; while sustained interaction of CD4 T cells with DCs and varying levels of IL-2 and IL-12 signaling lead to the differentiation of TH1 terminal effectors or TH1 memory precursors. TH1 memory precursors differentiate into TEM cells. TFH: Sustained interaction of CD4 T cells with B cells up-regulates Bcl-6 and represses T-bet expression, which favors TFH-cell differentiation or development of TCM cells. After pathogen clearance, the cells undergo contraction, and the fraction of TH1 and TFH cells that survive become long-lived memory cells of TCM, TEM, and TFH memory phenotypes. Upon secondary antigen encounter, TH1 memory CD4 T cells secondary expansion are thought to give rise to more TH1 like 2° effector cells, while TFH memory cells are more plastic and can give rise to TH1 and TFH 2° effector cells.