Memory CD4 T cells in influenza

Abstract

Influenza A virus is a significant cause of morbidity and mortality worldwide, particularly among young children and the elderly. Current vaccines induce neutralizing antibody responses directed toward highly variable viral surface proteins, resulting in limited heterosubtypic protection to new viral serotypes. By contrast, memory CD4 T cells recognize conserved viral proteins and are cross-reactive to multiple influenza strains. In humans, virus-specific memory CD4 T cells were found to be the protective correlate in human influenza challenge studies, suggesting their key role in protective immunity. In mouse models, memory CD4 T cells can mediate protective responses to secondary influenza infection independent of B cells or CD8 T cells, and can influence innate immune responses. Importantly, a newly defined, tissue-resident CD4 memory population has been demonstrated to be retained in lung tissue and promote optimal protective responses to an influenza infection. Here, we review the current state of results regarding the generation of memory CD4 T cells following primary influenza infection, mechanisms for their enhanced efficacy in protection from secondary challenge including their phenotype, localization, and function in the context of both mouse models and human infection. We also discuss the generation of memory CD4 T cells in response to influenza vaccines and its future implications for vaccinology.

Fig. 1

Overview of the primary CD4 T cell response and memory generation following Influenza infection. (a) Following Influenza infection, naïve DCs in the lung take up virus and virally-derived particles, driving their maturation and migration to the lung-draining lymph node. (b) Mature, activated DCs activate Influenza-specific naïve CD4 T cells trafficking through the lymph nodes. (c) CD4 effector cells traffic to the lung and can also reach the spleen via the circulation. (d) Effectors in the lung secrete effector cytokines and directly lyse virally-infected epithelial cells. (e) CD4 effectors also activate B cells and CD8 T cells in lymphoid tissues, allowing them to assume effector functions. (f) Responding effectors are retained as long live memory populations at diverse sites

Fig. 2

DC imprinting, tissue homing and tissue retention in effector and memory CD4 T cells. (a) Following Influenza infection, naïve CD4 T cells are activated in the lung-draining lymph node by lung-derived DCs which also imprint homing receptor expression allowing T cells to traffic to the lung. (b) Newly activated effectors reduce expression of CD62L and CCR7, allowing egress from the lymph node. In addition, lung homing molecules including CCR4, CXCR3, CCR5 and LFA-1 are upregulated, allowing cells to traffic to the lung by following a chemokine gradient. Integrins, such as LFA-1, facilitate tissue entry. (c) Activated effectors remain in the lung via expression of integrins, including LFA-1 and VLA-1. Factors such as inflammation and TCR signaling may trigger expression of CD69 is increased, though it is not clear. Expression of CD103 by CD8 Trm is triggered by TGF-β signaling