Understanding immunosenescence to improve responses to vaccines

Abstract

In the older adult, the benefits of vaccination to prevent infectious disease are limited, mainly because of the adaptive immune system's inability to generate protective immunity. The age-dependent decrease in immunological competence, often referred to as 'immunosenescence', results from the progressive deterioration of innate and adaptive immune responses. Most insights into mechanisms of immunological aging have been derived from studies of mouse models. In this Review, we explore how well such models are applicable to understanding the aging process throughout the 80-100 years of human life and discuss recent advances in identifying and characterizing the mechanisms that underlie age-associated defective adaptive immunity in humans.

Figure 1. Age and the human CD4 T cell repertoire

The cartoon illustrates the T cell receptor repertoire within the naïve and memory CD4 compartments with sizes of circles symbolizing different clonal sizes. By the end of the growth period, a diverse naïve repertoire has been established in the young adult. Irrespective of thymic activity, the naïve compartment only moderately decreases in size during the next decades in life while mostly maintaining overall diversity and distribution of clonal sizes. An abrupt contraction is seen in later life. Memory responses to latent infection with cytomegalovirus and herpes zoster virus (VZV) are established in the memory compartment, but behave very differently to aging. While clonal frequencies and sizes of VZV-specific clones decline with age (yellow circles), T cell clones specific for CMV (red circles) dominate the repertoire in the elderly and contribute to the contraction in diversity in the memory compartment.

Figure 2. T cell receptor desensitization in the elderly

One of the important regulators of T cell receptor activation thresholds is the dual-specific phosphatase DUSP6 that controls the initial ERK response and associated positive feedback loops after T cell stimulation. DUSP6 expression is regulated by miR181a. Due to a decline of miR181a, expression of DUSP6 increases with age resulting in the desensitization of the TCR signaling cascade.

Figure 3. Defective T-dependent B cell responses in the elderly

Elderly CD4⁺ memory T cells respond to T cell stimulation with increased expression of the dual-specific phosphatase DUSP4 because of increased activity of the metabolic master regulator AMPK. DUSP4 is a nuclear phosphatase that curtails sustained pERK and pJNK activity and impairs the ability of the T cell to provide help to B cells. As a consequence of defective CD40-ligand signaling, B cell activation and expression of the transcription factor E47 is impaired. Defective T cell help coincides with an age-associated intrinsic B cell defect to express E47 and as a consequence transcribe AID. As a consequence, B cell clonal expansion, immunoglobulin class switch recombination and hypermutation are impaired.

Figure 4. Age-associated expansion of terminally differentiated CD28-negative T cells

With increasing age, oligoclonal populations of terminally differentiated effector T cells accumulate that are frequently specific for latent viruses, in particular cytomegalovirus. These T cells differ in phenotype, function and survival from exhausted T cells that develop in response to highly replicating viruses.