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T-cell receptor (TCR) diversity, a prerequisite for immune system recognition of the universe of foreign antigens, is generated in the first two decades of life in the thymus and then persists to an unknown extent through life via homeostatic proliferation of naïve T cells. We have used next-generation sequencing and nonparametric statistical analysis to estimate a lower bound for the total number of different TCR beta (TCRB) sequences in human repertoires. We arrived at surprisingly high minimal estimates of 100 million unique TCRB sequences in naïve CD4 and CD8 T-cell repertoires of young adults. Naïve repertoire richness modestly declined two-to fivefold in healthy elderly. Repertoire richness contraction with age was even less pronounced for memory CD4 and CD8 T cells. In contrast, age had a major impact on the inequality of clonal sizes, as estimated by a modified Gini-Simpson index clonality score. In particular, large naïve T-cell clones that were distinct from memory clones were found in the repertoires of elderly individuals, indicating uneven homeostatic proliferation without development of a memory cell phenotype. Our results suggest that a highly diverse repertoire is maintained despite thymic involution; however, peripheral fitness selection of T cells leads to repertoire perturbations that can influence the immune response in the elderly.adaptive immune responses | aging | immunosenescence | T-cell homeostasis T he ability of the adaptive immune system to respond to a wide variety of pathogens depends on a large repertoire of unique T-cell receptors (TCRs). TCR diversity is generated by the random and imprecise rearrangements of the V and J segments of the TCR alpha (TCRA) and V, D, and J segments of the TCR beta (TCRB) genes in the thymus. Thymic production of T cells is the sole mechanism to generate TCR diversity. With

Background-In giant cell arteritis (GCA), vasculitic damage of the aorta and its branches is combined with a syndrome of intense systemic inflammation. Therapeutically, glucocorticoids remain the gold standard because they promptly and effectively suppress acute manifestations; however, they fail to eradicate vessel wall infiltrates. The effects of glucocorticoids on the systemic and vascular components of GCA are not understood. Methods and Results-The immunoprofile of untreated and glucocorticoid-treated GCA was examined in peripheral blood and temporal artery biopsies with protein quantification assays, flow cytometry, quantitative real-time polymerase chain reaction, and immunohistochemistry. Plasma interferon-␥ and interleukin (IL)-17 and frequencies of interferon-␥-producing and IL-17-producing T cells were markedly elevated before therapy. Glucocorticoid treatment suppressed the Th17 but not the Th1 arm in the blood and the vascular lesions. Analysis of monocytes/macrophages in the circulation and in temporal arteries revealed glucocorticoid-mediated suppression of Th17-promoting cytokines (IL-1␤, IL-6, and IL-23) but sparing of Th1-promoting cytokines (IL-12). In human artery-severe combined immunodeficiency mouse chimeras, in which patient-derived T cells cause inflammation of engrafted human temporal arteries, glucocorticoids were similarly selective in inhibiting Th17 cells and leaving Th1 cells unaffected. Conclusions-Two Clinical Perspective on p 915Glucocorticoids remain the gold standard of therapy; attempts to introduce steroid-sparing agents, including antitumor necrosis factor blockers, have not been successful. 3,4 Methotrexate may have minor benefits when given over prolonged periods. 5 In a double-blind, placebo-controlled study employing glucocorticoid pulse therapy, patients pulsed at diagnosis had fewer disease flares and discontinued therapy earlier than patients without initial pulse therapy. However, benefits of pulse glucocorticoids were delayed until 12 to 18 months into treatment. 6 Acetylsalicylic acid has a role as adjuvant therapy, partially by inhibiting inflammation and partially through antiplatelet effects. 7,8 Steroid withdrawal after Ͼ2 years of therapy is often accompanied by recurrence of inflammatory markers, and vascular inflammation persists despite glucocorticoid treatment. 9 -11 In essence, despite their prompt, impressive therapeutic effects, glucocorticoids fail to abrogate vasculitis. Improved disease management and avoidance of severe glucocorticoid side effects will require a better understanding of underlying immune abnormalities.Both the innate and adaptive immune system contribute to GCA pathogenesis. 12 Granulomatous inflammatory infiltrates composed of CD4 T cells, activated macrophages, and multinucleated giant cells induce intimal hyperplasia and luminal compromise. 13 In cell-depletion studies, dendritic cells (DCs) have emerged as the predominant antigen-presenting cell. 14,15 DCs are now recognized as an indigenous cell