![]() ![]() The limited repertoire diversity of NP- compared with PA-specific T cells predicts a lower number of clonotypes specific for NP compared with PA. Whereas the repertoire of Vβ8.3 + T cells specific for NP is limited and highly conserved between individual mice (termed a public repertoire), the repertoire of Vβ7 + T cells specific for PA is extremely diverse and varies among individual mice (termed a private repertoire) ( 36– 38). For example, the repertoire of CD8 T cells responding to two immunodominant influenza virus epitopes, NP 366-374/D b (NP), and PA 224-233/D b (PA), in C57BL/6 mice after primary influenza virus infection has been well characterized, and the responses to NP and PA are dominated by CD8 T cells expressing Vβ8.3 and Vβ7 elements in their TCRs, respectively ( 31– 36). Significant progress has been made in dissecting the diversity of the CD8 T cell response to several pathogens. Collectively, declining numbers and diversity of naive T cells emerging from the aged thymus, progressive increase in the proportion of antigen-experienced compared with naive T cells, and the development of large clonal expansions result in substantially reduced diversity among CD8 T cells in aged mice. The diversity of the memory repertoire is further compromised by the development of age-associated CD8 T cell clonal expansions, which can comprise 70–80% or more of the total CD8 T cell compartment in some aged animals ( 27– 30). The naive T cell repertoire also becomes increasingly constrained by the progressive accumulation of peripheral T cells exhibiting a memory phenotype, believed to be the result of the accumulated antigen experience of the individual ( 13, 20, 26). ![]() Fewer T cells are produced in the thymus, leading to reduced numbers of naive T cells in the periphery ( 25). However, several age-associated changes are thought to lead to reductions in both the size and diversity of the naive T cell repertoire. The functional diversity of the αβ TCR repertoire in the spleens of young mice has been estimated to be ∼2 × 10 6 clones, with ∼10 cells per clone ( 24). ![]() Thus, it has been speculated that declining T cell repertoire diversity associated with aging is a contributing factor to the impaired ability of aged individuals to mount effective immune responses to infections and vaccines ( 1, 5, 19– 23). The ability of individuals to generate effective T cell responses to newly encountered infections and to respond to vaccination requires the maintenance of a diverse repertoire of T cells ( 16– 18). It has been suggested that apparent declines in CD8 T cell effector function may instead be the consequence of age-associated changes in the composition of the CD8 T cell pool ( 13), consistent with reports that naive CD8 T cells from aged mice are fully functional ( 14, 15). Whereas the function of aged CD4 T cells has been extensively investigated and distinct defects defined, the impact of aging on CD8 T cell function is poorly understood ( 1, 3– 5, 11, 12). In addition, vaccines are considerably less effective in the elderly ( 6– 10). The elderly are more susceptible to infections, particularly to those caused by newly emerging and reemerging pathogens, and such infections are often of greater severity. It has been well-established that immunity declines with aging ( 1– 5). ![]() These observations have important implications for the design of vaccine strategies for the elderly. This study formally demonstrates in a mouse infection model that naturally occurring contraction of the naive T cell repertoire can result in impaired CD8 T cell responses to known immunodominant epitopes and decline in heterosubtypic immunity. Furthermore, a decline in repertoire diversity generally correlated with impaired responses to heterosubtypic challenge. These effects were also seen in young thymectomized mice, consistent with the role of the thymus in maintaining naive repertoire diversity. A preferential decline in reactivity to viral epitopes with a low naive precursor frequency was observed, in some cases leading to “holes” in the T cell repertoire. In this study, using the well-characterized mouse influenza virus model, we show that although comparable numbers of CD8 T cells are elicited in the lung and lung airways of young and aged mice after de novo infection, a majority of aged mice exhibit profound shifts in epitope immunodominance and restricted diversity in the TCR repertoire of responding cells. A diverse T cell repertoire is essential for a vigorous immune response to new infections, and decreasing repertoire diversity has been implicated in the age-associated decline in CD8 T cell immunity. ![]()
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