Age-Dependent Differences in T-Cell Responses to Influenza A Virus

Abstract

Respiratory infections from influenza A virus (IAV) cause substantial morbidity and mortality in children relative to adults. T cells play a critical role in the host response to IAV by supporting the innate and humoral responses, mediating cytotoxic activity, and promoting recovery. There are age-dependent differences in the number, subsets, and localization of T cells, which impact the host response to pathogens. In this article, we first review how T cells recognize IAV and examine differences in the resting T-cell populations between juveniles and adults. Next, we describe how the juvenile CD4⁺, CD8⁺, and regulatory T-cell responses compare with those in adults and discuss the potential physiologic and clinical consequences of the differences. Finally, we explore the roles of two unconventional T-cell types in the juvenile response to influenza, natural-killer T cells and γδ T cells. A clear understanding of age-dependent differences in the T-cell response is essential to developing therapies to prevent or reverse the deleterious effects of IAV in children.

Keywords: T cell; age-dependent; influenza; juvenile; viral pneumonia.

Figure 1.

Equivalent age groups of juvenile mice and humans. Approximate age ranges based on stages of lung development as described in Reference .

Figure 2.

Differences between juvenile and adult T-cell responses to influenza A virus. (A) Timeline depicting peak cell recruitment and cytokine levels in the lungs of juvenile and adult mice. (B) In addition to being delayed, the juvenile CD4⁺ and CD8⁺ T cell responses to influenza A virus are diminished compared with those of adults. Curves and time points approximated from References –, , . dpi = days post-infection.

Figure 3.

The juvenile T-cell response to influenza A virus. Recruitment of CD4⁺ and CD8⁺ T cells to the lungs is delayed and diminished relative to that of adults. Regulatory T cells are recruited in similar numbers. Production of inflammatory and suppressive cytokines IFN-γ and IL-10 is reduced. In neonates, there is a mixed T-helper cell type 1 (Th1) and Th2 response that contributes to increased levels of IL-4. As juveniles age, there is a shift to a Th1 response. In addition, neonates have less TCR variability, which increases as they age, as well as an increased propensity to induce stable Foxp3 expression, which decreases as they age. γδ T cells are a source of IL-17 in neonates and promote tissue recovery by inducing amphiregulin. DN NKT cells rapidly expand and exhibit the ability to suppress CD4⁺ T cells. DN NKT = double-negative natural-killer T cell.

Figure 4.

Comparison of T-cell response, viral clearance, and lung inflammation in adults and juveniles with influenza A infection. (A) In healthy adults, there is an early and robust T-cell response with mild inflammation that manifests as mild clinical disease. (B) In juveniles, there is a delayed and diminished T-cell response, resulting in prolonged, severe inflammation that manifests as severe clinical disease.