Abstract
T cells specific for persistent pathogens accumulate with age and express markers of immune senescence. In contrast, much less is known about the state of T cell memory for acutely infecting pathogens. Here we examined T cell responses to influenza in human peripheral blood mononuclear cells from older (>64) and younger (<40) donors using whole virus restimulation with influenza A (A/PR8/34) ex vivo. Although most donors had pre-existing influenza reactive T cells as measured by IFNγ production, older donors had smaller populations of influenza-responsive T cells than young controls and had lost a significant proportion of their CD45RA-negative functional memory population. Despite this apparent dysfunction in a proportion of the older T cells, both old and young donors' T cells from 2008 could respond to A/California/07/2009 ex vivo. For HLA-A2+ donors, MHC tetramer staining showed that a higher proportion of influenza-specific memory CD8 T cells from the 65+ group co-express the markers killer cell lectin-like receptor G1 (KLRG1) and CD57 compared to their younger counterparts. These markers have previously been associated with a late differentiation state or immune senescence. Thus, memory CD8 T cells to an acutely infecting pathogen show signs of advanced differentiation and functional deterioration with age. There was a significant negative correlation between the frequency of KLRG1+CD57+ influenza M1-specific CD8 T cells pre-vaccination and the ability to make antibodies in response to vaccination with seasonal trivalent inactivated vaccine, whereas no such trend was observed when the total CD8+KLRG1+CD57+ population was analyzed. These results suggest that the state of the influenza-specific memory CD8 T cells may be a predictive indicator of a vaccine responsive healthy immune system in old age.
Highlights
The aging human immune system is characterized by a variety of functional changes
To control for nonspecific responses of the peripheral blood mononuclear cells (PBMC) to a viral infection, we stimulated the human PBMC with a rodent RNA virus, Lymphocytic choriomeningitis virus (LCMV) Armstrong, as a control, as most humans would not be expected to have been exposed to this virus
We have demonstrated that an acute infection can result in the accumulation of late effector CD8 T cells that show markers that have been previously associated with immune senescence seen in late chronic infections such as with CMV
Summary
The aging human immune system is characterized by a variety of functional changes. In particular, the T cell population undergoes dramatic alterations in old age. Due to the seasonal nature of influenza incidence, individuals may be acutely infected multiple times over the course of their lifetime with a variety of influenza A strains, primarily of the H3N2 and H1N1 subtypes This presents a unique opportunity to examine a repeatedly boosted T cell response to an acute viral infection in the human population. Some literature has suggested that the cell-mediated compartment is less functional in older donors, these studies were done on bulk peripheral blood mononuclear cells (PBMC) and did not definitively identify a T cell population responsible for producing the protective or detrimental factors [25,26] To address this issue, a cohort of healthy young and older donors was recruited to examine the state of their cross-reactive influenza-specific memory T cells. T cells from both young and older donors recruited in 2008 responded to influenza A/PR8 but showed similar levels of reactivity to the A/ 2009 H1N1 strain, suggesting that the residual functional T cells in the older population may well be capable of providing protection to influenza strains sharing the conserved T cell epitopes
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