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.

Thymopoiesis in elderly human is associated with systemic inflammatory status

“…Jamieson et al (1999) reported that thymopoietic potential per cell, as measured by the quantification of T-cell receptor excision circles (TRECs), remains constant up to 56 years and those thymocytes recognize a broad range of antigens. The maintenance of the thymopoietic potential per cell was subsequently confirmed in both mice (Sempowski et al 2002) and humans (Sempowski et al 2000;Gruver et al 2007). Nevertheless, none of these works assessed a direct association between thymic function-related markers and peripheral naive subsets.…”

“…Among the clinical consequences of the immunosenescence are an increase in the frequency of infectious diseases (and, possibly, an increase in cancer and autoimmune diseases) (Yoshikawa 2000;Strindhall et al 2007) and poor response to vaccines (Gruver et al 2007). The loss of peripheral blood naive T cells is the bestknown effect of immunosenescence and the absence of response to vaccines has been ascribed, at least in part, to this decline (Aspinall et al 2007;Gruver et al 2007). The peripheral naive T-cell pool is maintained, preferably, by thymic lymphopoiesis as well as by the homeostatic mechanisms that account for the peripheral expansion (Cambier 2005;Cicin-Sain et al 2007).…”

Reduced naïve CD 8 + T ‐cell priming efficacy in elderly adults

“…In turn, the naïve T‐cell pool is generated by thymic output. However, the thymus atrophies with age, a process termed ‘thymic involution’ (Gruver et al ., 2007). This progressive decay in thymic function leads to a corresponding loss of naïve T‐cells and increased homeostatic proliferation within the naive T‐cell compartment (Kohler & Thiel, 2009; Sauce et al ., 2012).…”

Involvement of T-cell receptor-β alterations in the development of otosclerosis linked to OTSC2

“…42 In addition, changes in T-cell development could also increase or accelerate replicative senescence of T cells in the periphery resulting in altered competence of the immune system and increased vulnerability for autoimmune responses. 43 An important point in this study is that differences in T-cell parameters found for OTSC2 patients seem to be specific to this family, as they were generally not observed in patients with the complex form of otosclerosis. This implies that this is not a consequence of the otosclerosis disease pathology, but rather supports a causative role of the TRB locus in the pathology in this family.…”