The efficacy of the adaptive immune response declines dramatically with age, but the cell-intrinsic mechanisms driving immune aging in humans remain poorly understood. Immune aging is characterized by a loss of self-renewing naïve cells and the accumulation of differentiated but dysfunctional cells within the CD8 T cell compartment. Using ATAC-seq, we inferred the transcription factor binding activities correlated with naive and central and effector memory CD8 T cell states in young adults. Integrating our results with RNA-seq, we identified transcription networks associated with CD8 T cell differentiation, with prominent roles implicated for BATF, ETS1, Eomes, and Sp1. Extending our analysis to aged humans, we found that the differences between the memory and naive subsets were largely preserved across age, but that naive and central memory cells from older individuals exhibited a shift toward more differentiated patterns of chromatin openness. Additionally, aged naive cells displayed a loss in chromatin accessibility at gene promoters, largely associated with a decrease in NRF1 binding. This shift was implicated in a marked drop-off in the ability of the aged naive cells to transcribe respiratory chain genes, which may explain the reduced capacity of oxidative phosphorylation in older naïve cells. Our findings identify BATF- and NRF1-driven gene regulation as potential targets for delaying CD8 T cell aging and restoring function.

SUMMARY In an immune response, CD4+ T cells expand into effector T cells and then contract to survive as long-lived memory cells. To identify age-associated defects in memory cell formation, we profiled activated CD4+ T cells and found an increased induction of the ATPase CD39 with age. CD39+ CD4+ T cells resembled effector T cells with signs of metabolic stress and high susceptibility to undergo apoptosis. Pharmacological inhibition of ATPase activity dampened effector cell differentiation and improved survival, suggesting that CD39 activity influences T cell fate. Individuals carrying a low-expressing CD39 variant responded better to vaccination with an increase in vaccine-specific memory T cells. Increased inducibility of CD39 after activation may contribute to the impaired vaccine response with age.

Adaptive immune responses in humans rely on somatic genetic rearrangements of Ig and T-cell receptor loci to generate diverse antigen receptors. It is unclear to what extent an individual's genetic background affects the characteristics of the antibody repertoire used in responding to vaccination or infection. We studied the B-cell repertoires and clonal expansions in response to attenuated varicellazoster vaccination in four pairs of adult identical twins and found that the global antibody repertoires of twin pair members showed high similarity in antibody heavy chain V, D, and J gene segment use, and in the length and features of the complementarity-determining region 3, a major determinant of antigen binding. These twin similarities were most pronounced in the IgM-expressing B-cell pools, but were seen to a lesser extent in IgG-expressing B cells. In addition, the degree of antibody somatic mutation accumulated in the B-cell repertoire was highly correlated within twin pair members. Twin pair members had greater numbers of shared convergent antibody sequences, including mutated sequences, suggesting similarity among memory B-cell clonal lineages. Despite these similarities in the memory repertoire, the B-cell clones used in acute responses to ZOSTAVAX vaccination were largely unique to each individual. Taken together, these results suggest that the overall Bcell repertoire is significantly shaped by the underlying germ-line genome, but that stochastic or individual-specific effects dominate the selection of clones in response to an acute antigenic stimulus.H uman responses to infectious diseases or vaccinations rely on many different cell populations, soluble mediators, and interactions between cells. Prior studies of identical twins have highlighted aspects of human immunity that are heavily influenced by the germ-line genome, such as the proportions of particular leukocyte subsets (1). In addition to the germ line-encoded genes that affect the responses of immune cells, mammalian immune systems also make use of somatic genetic rearrangements to produce diverse repertoires of immunoglobulins (Igs) and T-cell receptors (TCRs) for specific recognition of foreign antigens. Antibody and TCR sequences are generated through the combinatorial use of a set of predetermined gene segments in the genome, as well as by more random exonuclease digestion of the ends of the gene segments, and addition of nontemplated bases at the junctions between gene segments. Clonal expansion of the populations of cells that recognize particular pathogens provides immune system memory of prior exposures.The germ-line genome sequence plays a role in the initial generation and selection of antibody and T-cell receptor repertoires in each individual, as demonstrated in prior work (2-6). Whether such genetic effects have a prominent effect on the clonal B-cell responses to particular pathogens or vaccinations is much less clear. In adult humans, it is possible that the accumulation of the effects of responses to prior antigenic exposures in...