Immunosenescence of ageing

Abstract

Ageing is a complex process that negatively impacts the development of the immune system and its ability to function. The mechanisms that underlie these age-related defects are broad and range from defects in the haematopoietic bone marrow to defects in peripheral lymphocyte migration, maturation and function. The thymus is a central lymphoid organ responsible for production of naïve T cells, which play a vital role in mediating both cellular and humoral immunity. Chronic involution of the thymus gland is thought to be one of the major contributing factors to loss of immune function with increasing age. It has recently been demonstrated that thymic atrophy is mediated by a shift from a stimulatory to a suppressive cytokine microenvironment. In this review we present an overview of the morphological, cellular and biochemical changes that have been implicated in the decline of thymic and peripheral immune function with ageing. We conclude with the clinical implications of age-associated immunosenescence to vaccine development for tumours and infectious disease. A fundamental understanding of the complex mechanisms by which ageing attenuates immune function will enable translational research teams to develop new therapies and vaccines specifically aimed at overcoming these defects in immunological function in the aged.

Figure 1

The human thymus across the lifespan. [A] Representative views of human thymus morphology throughout ageing. All tissue was formalin-fixed, paraffin-embedded and sections stained with haematoxylin and eosin and anti-keratin antibody [brown] to determine the percentage thymic epithelial space [each panel, ×25]. C, cortex; M, medulla; P, perivascular space. [B] Graphical depiction of the impact of age on human thymus morphology. Thymic epithelial space, pink; perivascular space, white. Reprinted with permission from reference [45]

Figure 2

Impact of ageing on human thymic output and peripheral naïve T cell pool. [A] Molecules of sjTREC/mg whole human thymus tissue. [B] Molecules of sjTREC/μg isolated peripheral blood mononuclear cell DNA [n = 100 donors, aged 6 months–80 years]

Figure 3

Impact of ageing on BALB/c mouse thymic output and splenic naïve T cell pools. [A] Molecules of mTREC/mg thymus tissue during ageing. Molecules of mTREC in naïve splenic CD4 [B] and CD8 [C] T cells in mice the age range 6–90 weeks [n = 3/group]. Data are mean ± SEM of three mice/group. *p < 0.05 compared to 6 week-old mice [44,45]

Figure 4

Schematic of cytokine stimuli that impact thymopoiesis