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Peripheral Blood and Granuloma CD4+CD28− T Cells Are a Major Source of Interferon-γ and Tumor Necrosis Factor-α in Wegener’s Granulomatosis

American Society for Investigative Pathology
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To elucidate whether the fraction of CD28− T cells within the CD4+ T-cell population is a major source of Th1-like and proinflammatory cytokine production driving Wegener’s granulomatosis (WG) granuloma formation, we analyzed the phenotype and functional characteristics of peripheral blood CD4+CD28− T cells and of T cells in granulomatous lesions of 12 patients with active WG. Surface markers and intracytoplasmic cytokine and perforin expression were assessed by flow cytometry. Cytokine secretion was measured by enzyme-linked immunosorbent assay. Immunohistological studies demonstrated interferon-γ and tumor necrosis factor-α cytokine positivity attributable to CD4+CD28− T cells in granulomatous lesions. Peripheral blood CD4+CD28− T cells expressed CD57, also found on natural killer cells, and intracytoplasmic perforin. They were generally CD25 (interleukin-2 receptor)-negative. CD18 (adhesion molecule β2-integrin) was strongly up-regulated on CD4+CD28− T cells, whereas only a minority of CD4+CD28+ T cells expressed CD18. CD4+CD28− T cells appeared as a major source of interferon-γ and tumor necrosis factor-α. In contrast, CD4+CD28+ T cells were able to produce and secrete a wider variety of cytokines including interleukin-2. One-quarter of CD4+CD28+ T cells expressed the activation marker CD25, but they lacked perforin. Thus, CD4+CD28− T cells appeared more differentiated than CD4+CD28+ T cells. They displayed Th1-like cytokine production and features suggestive of the capability of CD4+ T-cell-mediated cytotoxicity. CD4+CD28− T cells may be recruited into granulomatous lesions from the blood via CD18 interaction, and may subsequently promote monocyte accumulation and granuloma formation through their cytokine secretion in WG.

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