With increasing age, the human immune system undergoes characteristic changes, termed immunosenescence, which lead to increased incidence and severity of infectious diseases and to insufficient protection following vaccination. Functional defects and altered frequencies of innate and adaptive immune cells impair local responses at the site of vaccine injection, hamper the generation of primary responses to neoantigens, prevent the effective induction of memory lymphocytes, and decrease the effect of booster vaccination. As a result, antibody responses of elderly vaccinees are weaker and decline faster, and long-term protective effects of vaccination cannot be taken for granted in elderly persons. Improved vaccination strategies, new adjuvants, and new vaccines that specifically target the aged immune system will help to overcome the limitations of immunosenescence and ensure a better protection of the vulnerable elderly population.

Old age is associated with characteristic changes of the immune system contributing to higher incidence and severity of many infectious diseases. Particularly within the T cell compartment latent infection with human Cytomegalovirus (CMV) is contributing to and accelerating immunosenescence. However, latent CMV infection and reactivation usually does not cause overt symptoms in immunocompetent elderly persons indicating immunological control of disease. Little is still known about the clonal composition of CMV-specific T cell responses in donors of different age. We therefore analyzed CD8 + T cells specific for an immunodominant pp65-derived nonamerpeptide (NLVPMVATV; CMV NLV ) in different age-groups. Independent of donor age CMV NLVspecific CD8 + T cells preferentially use the V beta family 8. This family has monoclonal expansions in the majority of donors after stimulation of CD8 + T cells with the peptide. By sequencing the CDR3 region of the T cell receptor we demonstrated that CMV NLV -specific, BV8 + CD8 + T cells share the conserved CDR3-sequence motif SANYGYT in donors of all age groups. Interestingly, a second conserved clonotype with the CDR3-sequence motif SVNEAF appears in middle-aged and elderly donors. This clonotype is absent in young individuals. The age-related clonotype SVNEAF binds to the pMHC-complex with higher avidity than the clonotype SANYGYT, which is predominant in young adults. The dominance of this high avidity clonotype may explain the lack of overt CMV-disease in old age.

APCs operate frequently under oxidative stress induced by aging, tissue damage, pathogens, or inflammatory responses. Phagocytic cells produce peroxides and free-radical species that facilitate pathogen clearance and can in the case of APCs, also lead to oxidative modifications of antigenic proteins and peptides. Little information is available presently about the consequences of such modifications on the immune response. To model oxidative modification of an immunodominant antigenic peptide, we oxidized the methionine residue of the human CMV pp65(495-503) (NLVPMVATV) peptide. Such modifications of an antigenic peptide can affect MHC binding or TCR recognition. Using binding and dissociation assays, we demonstrate that oxidative modification of the CMVpp65(495-503) peptide leads to a decreased binding of the pMHC complex to the TCR, whereas binding of the peptide to the MHC class I molecule is not impaired. Additionally, we show that CD8(+) T cells have a decreased proliferation and IFN-gamma production when stimulated with oxidized CMVpp65(495-503) peptide. Spectratyping the antigen-binding site of the TCR of responding T cells demonstrates that the CMVpp65(495-503) and the CMVoxpp65(495-503) peptides preferentially stimulate BV8 T cells. Sequencing of this dominant BV family reveals a highly conserved CDR3 amino acid motif, independent of the mode of stimulation, demonstrating the recruitment of the same T cell clonotypes. Our results suggest that oxidative modification of antigenic peptides may affect T cell responses severely by binding T cell clones with different affinity. This may lead to an altered immune response against infectious agents as well as against tumor or autoantigens under oxidative stress conditions.

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CD4 + CD8 + T cells in young and elderly humans. Comment on Macchia I, Gauduin MC, Kaur A, Johnson RP. Expression of CD8a identifies a distinct subset of effector memory CD4 + T lymphocytes. Immunology 2006; 119:232-42 In a recent article by Macchia et al., 1 the frequency, phenotype and function of peripheral CD4 + CD8 + T cells in rhesus macaques were described. The authors demonstrate that the double-positive population is mainly CD4 hi CD8 lo and that 78% of this population exhibits an effector memory phenotype. They also state that the frequency of double-positive T cells does not change with age. No data are available about the characteristics of peripheral CD4 hi CD8 lo or CD4 lo CD8 hi T cells in young and elderly persons, so it is difficult to assess the significance of the data by Maccia et al. 1 for humans. We will therefore illustrate similarities and differences of peripheral CD4 + CD8 + T-cell subsets between rhesus macaques and humans and address the effect of age.As demonstrated by Laux et al., 2 we found a significant increase in the frequency of total peripheral CD4 + CD8 + T cells in the elderly compared to young persons (Table 1). Interestingly, CD4 + CD8 + T cells were enriched within the large cells of the lymphocyte population. Within the CD4 + CD8 + T-cell population we distinguished between CD4 hi CD8 lo , which expressed the CD8aa receptor and CD4 lo CD8 hi T cells which expressed the CD8ab receptor (Fig. 1a). Immunofluorescence surface staining was performed as described elsewhere. 3 Briefly, the antibodies used were CD3-peridinin chlorophyll protein, CD4-fluorescein isothiocyanate, CD8a-allophycocyanin and CD8b-phycoerythrin. Our data demonstrate that the number of CD4 lo CD8 hi T cells was increased in elderly compared to young persons, while the number of CD4 hi CD8 lo T cells was not affected by age (Table 1). In contrast to rhesus macaques, no dominance of the CD4 hi CD8 lo T cells was observed in either young or elderly persons, but a high variability in the frequency of CD4 hi CD8 lo T cells in both the young (0AE06-1AE15%) and the elderly (0AE05-1AE85%, Fig. 1a All participants had given their informed written consent and the study was approved by the local ethical committee. SummaryPeripheral CD4 + CD8 + T cells have been described in animals as well as in humans. Two distinct populations can be distinguished, namely CD4 lo CD8 hi and CD4 hi CD8 lo T cells. We demonstrate here that the increase in the number of peripheral CD4 + CD8 + T cells in the elderly is the result of an increase of the CD4 lo CD8 hi T-cell population. While the phenotype of CD4 lo CD8 hi and CD4 hi CD8 lo T cells was very similar in young persons, CD4 hi CD8 lo , T cells from elderly subjects expressed a more differentiated phenotype and produced less interleukin-2 compared to CD4 lo CD8 hi T cells. In conclusion, our results suggest that aging leads to a phenotypic and functional difference between CD4 + CD8 + T-cell subsets. It may therefore be of relevance to distinguish between these subsets befor...