Immunosenescence: A systems-level overview of immune cell biology and strategies for improving vaccine responses

Abstract

Immunosenescence contributes to a decreased capacity of the immune system to respond effectively to infections or vaccines in the elderly. The full extent of the biological changes that lead to immunosenescence are unknown, but numerous cell types involved in innate and adaptive immunity exhibit altered phenotypes and function as a result of aging. These manifestations of immunosenescence at the cellular level are mediated by dysregulation at the genetic level, and changes throughout the immune system are, in turn, propagated by numerous cellular interactions. Environmental factors, such as nutrition, also exert significant influence on the immune system during aging. While the mechanisms that govern the onset of immunosenescence are complex, systems biology approaches allow for the identification of individual contributions from each component within the system as a whole. Although there is still much to learn regarding immunosenescence, systems-level studies of vaccine responses have been highly informative and will guide the development of new vaccine candidates, novel adjuvant formulations, and immunotherapeutic drugs to improve vaccine responses among the aging population.

Keywords: Adjuvants; Aging; Immunity; Immunosenescence; Senolytics; Systems biology; Vaccinology.

Figure 1.. Immune cell populations and the effects of immunosenescence on cellular function.

Arrows denote crosstalk/signaling between cell populations, illustrating the potential for dysfunction in a single population to affect the function of numerous other cell subsets. Innate immune cells (neutrophils, macrophages/monocytes, dendritic cells, NK cells) are all involved with signaling and recruitment of other innate cell populations during the early phases of an immune response. Macrophages and dendritic cells bridge the gap from innate to adaptive immunity via antigen presentation and stimulatory signaling to cognate T-cells, and disruption in either of these functions can drastically compromise adaptive responses. Helper T-cells are critical for subsequent development of robust B-cell antibody responses, further illustrating how dysfunction among cells at both the innate and adaptive level can affect the overall outcomes of an immune response.

Figure 2.. Genetic regulatory mechanisms affected by immunosenescence.

Regulation of cellular function is often mediated by changes at the genetic level. Covalent modifications on histone tails modulate the accessibility of DNA for transcription, methylation of CpG sequences in promoter regions can affect transcription factor binding, and miRNA expression can modulate gene silencing through a number of different mechanisms at the post-transcriptional level. All of these have been shown to be differentially regulated to some capacity with aging and associated with changes in immune cell function.