CD4⁺ T‐cell memory: generation and multi‐faceted roles for CD4⁺ T cells in protective immunity to influenza

Abstract

SummaryWe have outlined the carefully orchestrated process of CD4 + T-cell differentiation from naïve to effector and from effector to memory cells with a focus on how these processes can be studied in vivo in responses to pathogen infection. We emphasize that the regulatory factors that determine the quality and quantity of the effector and memory cells generated include (i) the antigen dose during the initial T-cell interaction with antigen-presenting cells; (ii) the dose and duration of repeated interactions; and (iii) the milieu of inflammatory and growth cytokines that responding CD4 + T cells encounter. We suggest that heterogeneity in these regulatory factors leads to the generation of a spectrum of effectors with different functional attributes. Furthermore, we suggest that it is the presence of effectors at different stages along a pathway of progressive linear differentiation that leads to a related spectrum of memory cells. Our studies particularly highlight the multi-faceted roles of CD4 + effector and memory T cells in protective responses to influenza infection and support the concept that efficient priming of CD4 + T cells that react to shared influenza proteins could contribute greatly to vaccine strategies for influenza. Overview and historyOver the past decade, others and we have concluded that naïve precursor T cells must undergo many steps of division and differentiation before they acquire the effector functions necessary for their many regulatory activities (1). One of these activities is 'help' for B cells, which promotes B-cell isotype switching, somatic mutation, and differentiation in germinal centers to plasma cells and memory cells (2-4). Another key regulatory activity carried out by CD4 + T cells involves help for naïve CD8 + T cells to promote their optimum differentiation into cytotoxic effectors and memory cells and to support their maintenance (5-7). In addition, there are a host of other regulatory effects of CD4 + effectors on macrophages as well as other antigenpresenting cells (APCs). These CD4 + T-cell functions are mediated by surface coreceptors on the effector cells, including CD40L, CD28, cytotoxic T-lymphocyte antigen-4, etc., that interact with receptors on B cells, dendritic cells, macrophages, or other APCs, and by potent cytokines secreted by the CD4 + effectors upon recognition of antigen on APCs.CD4 + T-cell effectors represent a collection of distinct subsets characterized in part by their abilities to produce different patterns of cytokines. The two best characterized subsets are designated T-helper 1 (Th1), producing interferon-γ (IFN-γ), and Th2, producing interleukin-4 (IL-4), IL-5, and IL-13 as 'signature' cytokines. Recently, evidence has accumulated for a third . Most probably the APCs that stimulate the naïve CD4 + T cells are also the initial source of cytokines that imprint these subsets in situ (11). It is also increasingly accepted that the polarizing cytokines secreted by the APCs are dictated by the context of the antigen, be it from a pathogen or...

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