The ability to mount protective immune responses depends on the diversity of T cells. T cell diversity may be compromised by the declining thymic output of new T cells. The aging process imposes a threat to diversity, because thymic function deteriorates. In this study we have examined the relationship between thymic production, homeostatic T cell proliferation and TCR β-chain diversity in young (∼25 years), middle-aged (∼60 years), and elderly adults (∼75 years). TCR excision circles (TREC) as a marker of thymic output exponentially decreased by >95% between 25 and 60 years of age. The frequency of Ki67⁺ cycling CD4 T cells remained steady, and surprisingly, the diversity of the naive CD4 T cell repertoire was maintained at ∼2 × 10⁷ different TCR β-chains. After the age of 70 years, TRECs only slightly declined, but homeostatic proliferation doubled. The diversity of the T cell pool drastically contracted to 200,000 TCR β-chains. Also, the phenotypic distinction between naive and memory CD4 T cells became fuzzy. The collapse in CD4 T cell diversity during the seventh and eighth decades indicates substantial T cell loss and implies that therapeutic measures to improve vaccine responses will have to include strategies for T cell replenishment.

Human T cell function declines with age, reducing the ability of vaccines to protect the elderly against infectious disease. In this issue, Jörg Goronzy and his colleagues shed light on the mechanism by which naive CD4+ T cell responses are impaired in elderly individuals. The researchers show that miR-181a is reduced in these cells in older individuals. This results in increased expression of DUSP6, a phosphatase that dampens ERK signaling, which is necessary for optimal T cell receptor sensitivity to antigen. The ability of the human immune system to respond to vaccination declines with age. We identified an age-associated defect in T cell receptor (TCR)-induced extracellular signal–regulated kinase (ERK) phosphorylation in naive CD4+ T cells, whereas other signals, such as ζ chain–associated protein kinase 70 (ZAP70) and phospholipase C-γ1 phosphorylation, were not impaired. The defective ERK signaling was caused by the dual specific phosphatase 6 (DUSP6), whose protein expression increased with age due to a decline in repression by miR-181a. Reconstitution of miR-181a lowered DUSP6 expression in naive CD4+ T cells in elderly individuals. DUSP6 repression using miR-181a or specific siRNA and DUSP6 inhibition by the allosteric inhibitor (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one improved CD4+ T cell responses, as seen by increased expression of activation markers, improved proliferation and supported preferential T helper type 1 cell differentiation. DUSP6 is a potential intervention target for restoring T cell responses in the elderly, which may augment the effectiveness of vaccination.

Introduction: Interleukin (IL)-17 is a proinflammatory cytokine that is produced largely by a unique CD4⁺ T-helper (Th) subset called Th17 cells. The development of Th17 cells is suppressed by interferon (IFN)-γ produced by Th1 cells, suggesting cross-regulation between Th17 and Th1 cells. Thus, this study analyzed the balance of CD4⁺ Th17 and Th1 cell responses in peripheral blood from patients with systemic lupus erythematosus (SLE) and healthy subjects. Methods: Twenty-five adult patients with SLE and 26 healthy subjects matched for gender and age (± 2 years) were recruited. Peripheral blood mononuclear cells (PBMCs) from patients and healthy subjects were stimulated for 4 h ex vivo with phorbol myristate acetate (PMA) and ionomycin. The frequency of CD4⁺ T cells producing IL-17 and/or IFN-γ was measured by using flow cytometry. Expression of Th17-associated chemokine receptors CCR4 and CCR6 on CD4⁺ T cells as well as plasma levels of Th17-polarizing cytokines were assessed. Disease activity was evaluated by the SLE disease activity index score (SLEDAI). Unpaired t test and Pearson correlation were used for statistical analyses. Results: Patients with SLE had an increased frequency of CD4⁺IL-17⁺ T cells compared with healthy subjects. However, the frequency of CD4⁺IFN-γ⁺ T cells was similar between the two groups, indicating an altered balance of Th17 and Th1 cell responses in SLE. Patients with SLE also had an increased frequency of CD4⁺CCR4⁺CCR6⁺ T cells that are known to produce IL-17. The frequency of CD4⁺IL-17⁺ T cells and CD4⁺CCR4⁺CCR6⁺ T cells correlated with disease activity. In measuring plasma levels of the Th17-polarizing cytokines, levels of IL-6 were higher in patients with SLE than in healthy subjects, although levels of IL-1β, IL-21, IL-23, and transforming growth factor (TGF)-β were not different between the two groups. Conclusions: We demonstrate an enhanced Th17 cell response that correlates with disease activity in patients with SLE, suggesting a role for IL-17 in the pathogenesis of lupus. Our data indicate that the mechanisms involved in balancing Th1 and Th17 regulation, as well as in producing IL-6, are aberrant in SLE, leading to an increased Th17 response. We suggest that CCR4 and CCR6 expression on CD4⁺ T cells should be considered as markers of disease activity, and that IL-17 blocking may offer a therapeutic target in SLE.

FOXP3-positive regulatory T (Treg) cells are a unique subset of T cells with immune regulatory properties. Treg cells can be induced from non-Treg CD4⁺ T cells (induced Treg [iTreg] cells) by TCR triggering, IL-2, and TGF-β or retinoic acid. 1,25-Dihyroxyvitamin D₃ [1,25(OH)₂VD₃] affects the functions of immune cells including T cells. 1,25(OH)₂VD₃ binds the nuclear VD receptor (VDR) that binds target DNA sequences known as the VD response element (VDRE). Although 1,25(OH)₂VD₃ can promote FOXP3 expression in CD4⁺ T cells with TCR triggering and IL-2, it is unknown whether this effect of 1,25(OH)₂VD₃ is mediated through direct binding of VDR to the FOXP3 gene without involving other molecules. Also, it is unclear whether FOXP3 expression in 1,25(OH)₂VD₃-induced Treg (VD-iTreg) cells is critical for the inhibitory function of these cells. In this study, we demonstrated the presence of VDREs in the intronic conserved noncoding sequence region +1714 to +2554 of the human FOXP3 gene and the enhancement of the FOXP3 promoter activity by such VDREs in response to 1,25(OH)₂VD₃. Additionally, VD-iTreg cells suppressed the proliferation of target CD4⁺ T cells and this activity was dependent on FOXP3 expression. These findings suggest that 1,25(OH)₂VD₃ can affect human immune responses by regulating FOXP3 expression in CD4⁺ T cells through direct VDR binding to the FOXP3 gene, which is essential for inhibitory function of VD-iTreg cells.