Abstract
Chronic low-grade inflammation and reduced lymphocyte potency are implicated in the pathogenesis of major illnesses associated with aging. Whether this immune phenotype results from a loss of cell-mediated regulation or intrinsic dysregulated function of effector T cells (Teffs) requires further research. Here, we report that, as compared with young C57BL6 mice, old mice show an increased frequency of CD4+CD62L− Teffs with a dysregulated activated phenotype and markedly increased effector functions. Analysis of the frequency and suppressive function of CD4+FoxP3+ regulatory T cells (Tregs) indicates an increase in the frequency of FoxP3+ T cells with aging which, however, occurs within the CD4+CD25− T cells. Furthermore, whereas Tregs from young and old mice similarly suppress Teffs from young mice, both have a compromised suppressive capacity of Teffs from old mice, a phenomenon which is partially recovered in the presence of IL-2-producing CD4+CD62L+ non-Teffs. Finally, we observed that Teff subsets from old mice are enriched with IL-17A-producing T cells and exhibit intrinsically dysregulated expression of genes encoding cell-surface molecules and transcription factors, which play a key role in T-cell activation and regulation. We, thus, demonstrate an age-related impairment in the regulation of effector CD4 T cells, which may underlie the higher risk for destructive inflammation associated with aging.
Highlights
The significant deterioration of the immune system with age, which is known as immunosenescence and results from lifelong chronic antigenic stress [1, 2], increases the incidence and susceptibility to infection and degenerative diseases at older ages [3, 4]
Stimulated CD4+ T cells obtained from old mice secreted significantly higher levels of the effector cytokines interferon gamma (IFN-γ), IL-17A, and IL-10, as compared with the stimulated CD4+ T cells obtained from young mice (Figure 1H)
Since we examined the activity of regulatory T cells (Tregs) in the absence of the CD4+CD62L+ subset, which is the major source of IL-2 within CD4+CD25− T cells (Figure 1J), we examined their role in the Treg suppression assay [32]
Summary
The significant deterioration of the immune system with age, which is known as immunosenescence and results from lifelong chronic antigenic stress [1, 2], increases the incidence and susceptibility to infection and degenerative diseases at older ages [3, 4]. Immunosenescence results in immune deficiency, it is associated with chronic low-grade inflammation and with a higher risk of developing age-related diseases that usually, if not always, Abbreviations: Teffs, effector T cells; Tregs, regulatory T cells; IFN-γ, interferon gamma; RORγ, RAR-related orphan receptor; TGF-βR1, transforming growth factor beta receptor 1; PD1, programmed cell death protein 1; CTLA-4, cytotoxic T-lymphocyteassociated protein 4; ICOS, inducible T-cell costimulatory; GAPDH, glyceraldehyde 3-phosphate dehydrogenase. Aging Promotes Dysregulated Effector Functions share an inflammatory pathogenesis [5, 6]. The mechanism underlying this “Janus head” of immunosenescence is multidimensional and involves both the innate and adaptive immune compartments [7, 8]. The frequency of the highly pro-inflammatory Th17 T cells, which are implicated in several mouse models of autoimmune diseases [16,17,18], is more prevalent in aged mice [19]
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