Editorial: Profiling senescent influenza-specific T cells in the elderly

Influenza causes annual epidemics that are associated with significant morbidity and mortality, especially in infants and the elderly. From 1976 to 2007, there have been nearly 24,000 influenza-associated deaths reported in the United States each year (range: 3349–48,614 deaths/year), and people 65 years of age account for 88% of the annual influenza-associated deaths with underlying pneumonia and influenza causes [1]. To reduce the burden of influenza-associated morbidity and mortality, annual influenza vaccines are recommended for all persons over 6 months of age. The overall effectiveness of influenza vaccines varies by year, circulating virus type, and importantly, by age. A recent, comprehensive meta-analysis revealed that the pooled efficacy of trivalent-inactivated influenza vaccination is 59% in adults, aged 18–65 years [2], which is similar to the estimated 56% overall vaccine efficacy for the 2012–13 season against influenza A and B virus infections, recently released by the Centers for Disease Control and Prevention [3]. However, the adjusted, age-stratified vaccine efficacy for 2012– 2013 was only 9% for persons aged 65 years [3], and despite a large increase in vaccination coverage, this may, at least partly, explain why influenza-associated deaths have remained relatively stable in the elderly [4, 5]. In 2011, the U.S. Census estimated that 41 million individuals (i.e., 13% of the population) were over the age of 65. By 2030, this number is projected to increase to 70 million ( 20% of the population) [6]. Indeed, persons over the age of 85 are the fastest-growing segment of the population [7]. Given that older individuals are at increased risk of severe disease and the low efficacy of current influenza vaccines in this population, there is an urgent need to learn more about the aged immune system and to provide better vaccinemediated protection for the elderly. To begin to dissect the underlying mechanisms of poor cellular immunity observed in the aged population, Dolfi et al. [8] have examined age-related changes in the phenotype and functional attributes of total CD8 T cells, as well as within influenzaand CMVspecific T cell subsets, in this issue of Journal of Leukocyte Biology. Phenotypic analysis of inhibitory receptors showed that there was a significant increase in the expression of senescence (e.g., CD57, KLRG1) and exhaustion (e.g., PD-1) markers in total CD8 T cells from the aged population. However, aged individuals have a higher frequency of memory T cells, and when gating specifically on the memory CD8 T cell population, the differences in the expression CD57 and KLRG1 were no longer apparent, whereas the increased expression of PD-1 still remained. These phenotypic changes were accompanied with increased expression of T-box transcription factors, T-bet and Eomes, which are known to control CD8 T cell differentiation into effector and memory T cells, respectively. In contrast, when influenza-specific CD8 T cells were examined, the expression pattern of inhibitory receptors was markedly different from that observed when analyzing the total, non-naive CD8 T cells, and somewhat unexpectedly, PD-1 expression was lower in influenza-specific T cells from the aged cohort when compared with the younger subjects. This provides a cautionary note when performing human subject research, as it shows that broad analysis of CD8 T cell phenotype or function, based on T cells with unknown antigenic history, may not be predictive of the phenotype or function of defined, virus-specific CD8 T cell populations. This is likely a result of unrelated viruses, such as CMV or influenza triggering memory T cell responses of a very different phenotype and antiviral activity, and this cannot be discerned when total memory T cell populations are combined for analysis without first determining their antigen specificity. Interestingly, older individuals had a significantly higher frequency of IFNTNFCD8 T cells in response to conserved influenza matrix and nucleoprotein epitopes. However, the cytotoxic potential of these antigen-specific cells, as measured by the ability to degranulate (via up-regulation of CD107 on the cell surface), was reduced significantly