Age-related accumulation of T cells with markers of relatively stronger autoreactivity leads to functional erosion of T cells

Abstract

BackgroundThymic involution is a prominent characteristic of an aging immune system. When thymic function is reduced/absent, the peripheral T cell pool is subject to the laws of peripheral T cell homeostasis that favor survival/expansion of T cell receptors with relatively higher functional avidity for self-peptide/MHC complexes. Due to difficulties in assessing the TCR avidity in polyclonal population of T cells, it is currently not known whether high avidity T cells preferentially survive in aging individuals, and what impact this might have on the function of the immune system and development of autoimmune diseases.ResultsThe phenotype of T cells from aged mice (18-24 months) indicating functional TCR avidity (CD3 and CD5 expression) correlates with the level of preserved thymic function. In mice with moderate thymic output (> 30% of peripheral CD62Lhi T cells), T cells displayed CD3lowCD5hi phenotype characteristic for high functional avidity. In old mice with drastically low numbers of CD62Lhi T cells reduced CD5 levels were found. After adult thymectomy, T cells of young mice developed CD3lowCD5hi phenotype, followed by a CD3lowCD5low phenotype. Spleens of old mice with the CD3low/CD5hi T cell phenotype displayed increased levels of IL-10 mRNA, and their T cells could be induced to secrete IL-10 in vitro. In contrast, downmodulation of CD5 was accompanied with reduced IL-10 expression and impaired anti-CD3 induced proliferation. Irrespective of the CD3/CD5 phenotype, reduced severity of experimental allergic myelitis occurred in old mice. In MTB TCRβ transgenic mice that display globally elevated TCR avidity for self peptide/MHC, identical change patterns occurred, only at an accelerated pace.ConclusionsThese findings suggest that age-associated dysfunctions of the immune system could in part be due to functional erosion of T cells devised to protect the hosts from the prolonged exposure to T cells with high-avidity for self.

Aging diminishes the resistance of AO rats to EAE: putative role of enhanced generation of GM-CSF Expressing CD4+ T cells in aged rats

“…The analyses of CD4+ TCRαβ + lymphocyte profile in age-matched rats immunized with CFA only showed that this difference was specific to immunization with specific (auto)antigens. This was consistent with data indicating the accumulation of T cells with autoreactive specificities with aging in both humans and experimental animals [ 20 , 64 ]. This phenomenon has been related to the erosion of naïve T cell pool with aging, and consequent residual T-cell proliferation to reconstitute their nearly normal numbers [ 65 ].…”

“…This phenomenon has been related to the erosion of naïve T cell pool with aging, and consequent residual T-cell proliferation to reconstitute their nearly normal numbers [ 65 ]. In this compensatory event T cells with higher avidity for self-peptide/MHC complexes enjoy advantage and expand more relative to the low avidity T cells [ 20 ]. This leads to the accumulation of high avidity T cells, which is potentially dangerous due to increased risk of autoimmune disorders [ 66 ].…”

Epidemiological Study of Adult-Onset Myasthenia Gravis in the Area of Belgrade (Serbia) in the Period 1979–2008

“…However, the influence of population aging due to increasing life expectancy cannot be excluded. Moreover, significant increases in MG incidence rates in the elderly could be partially explained by increased susceptibility to autoimmune diseases in older persons due to aging of the immune system [21] or the influence of certain environmental factors. …”

Aging of thymus gland and immune system

“…38 Premature aging of the immune system and incidence of cytomegalovirus (CMV) infection were sequelae of thymectomy during infancy 39 In reduced or absent thymic function and aged immune system, the peripheral T cell population becomes regulated through the persistence and expansion of the T cell receptors together with their increased functional greediness for own peptides. 40 Progressive decline in immunity with aging results in increased incidence of infections and impaired responses to vaccines. 41 With the sixth decade of life, the human immune system begins profound aging-related changes which ultimately ends in a state of immunosenescence.…”