Background/Purpose:  Advancing age is the strongest risk factor for GCA, a disease that exclusively affects individuals >50 years of age. The immune system undergoes dramatic restructuring with aging, but aging-related cellular and molecule defects that predispose to GCA have remained undefined. In general, immune aging is associated with the declining ability to generate antigen-specific immune responses and the increasing propensity for inflammatory activity. Here, we have examined whether patients with GCA lack anti-inflammatory regulatory mechanisms in the adaptive immune system, rendering them susceptible to unopposed inflammation and tissue damage.

Methods:  Patients with biopsy-positive GCA and age-matched healthy controls were enrolled into the study. Immunosuppressive T regulatory cells (Treg) in the CD4 and CD8 compartment were quantified by phenotypic and functional analysis. Expression of the lineage-determining transcription factor FoxP3 and the immunosuppressive NADPH oxidase 2 (NOX2) was determined by flow cytometry. Immunosuppression was measured by monitoring the pool of phosphorylated signaling molecules (pZAP70) in stimulated target cells.

Results:  Frequency of CD4⁺FoxP3⁺ Tregs was maintained in GCA patients compared to controls (p=0.207). To assess the population of CD8⁺FoxP3⁺ Tregs, we defined the phenotype of such cells as CD39⁺, CD26^– and CCR7⁺ and identified the oxidase NOX2 as their functional element. CD8⁺CCR7⁺NOX2⁺ Tregs were distinctly low in patients with GCA (p<0.001). By comparing untreated and treated patients, we found that anti-inflammatory therapy did not restore this functional T cell subset (p=0.591). Comparative studies in patients with other inflammatory conditions (e.g. small vessel vasculitis, psoriatic arthritis) indicated that the defect was selective for GCA. Understanding the functional implications of CD8 Treg deficiency required definition of the molecular mechanism underlying their suppressive activity and their distribution in the immune system. CD8 Tregs were positioned in the T-cell zones of secondary lymphoid tissues and suppressed the activation of CD4 T cells by the targeted release of NOX2-containing microvesicles (p<0.001). Exosomes generated from CD8 Tregs were able to mediate the suppressive function and limited the activation of CD4 T cells (p<0.001). In healthy individuals, CD8 Tregs lost NOX2 expression with progressive age (p<0.001). This age-related loss of Treg function was markedly accelerated in GCA patients (p<0.001).

Conclusion: In humans, CD8 Treg cells function by packaging the enzyme NOX2 into microvesicles and transferring them onto neighboring CD4 T cells, to effectively suppress their clonal expansion. In healthy aging, CD8⁺NOX2⁺ Tregs decline with age. In patients with GCA, such CD8⁺NOX2⁺ Tregs are reduced to minimal frequencies. With the loss of CD8⁺NOX2⁺ Tregs, GCA patients lack an immunoinhibitory principal, exposing them to uncontrolled expansion of proinflammatory CD4 T cells. Recovering the function of CD8⁺NOX2⁺ Tregs in GCA may allow for reparative instead of immunocompromising therapy.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/age-related-defects-in-the-immune-system-of-patients-with-gca/