Peripheral blood and granuloma CD4(+)CD28(-) T cells are a major source of interferon-gamma and tumor necrosis factor-alpha in Wegener's granulomatosis.
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-gamma and tumor necrosis factor-alpha 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 beta(2)-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-gamma and tumor necrosis factor-alpha. 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.
Komocsi
Andras
A
Department of Rheumatology, University of Luebeck, Luebeck, Germany.
Lamprecht
Peter
P
Csernok
Elena
E
Mueller
Antje
A
Holl-Ulrich
Konstanze
K
Seitzer
Ulrike
U
Moosig
Frank
F
Schnabel
Armin
A
Gross
Wolfgang Ludwig
WL
D018106:CD28 Antigens / Q000032:analysis; D015704:CD4 Antigens / Q000032:analysis; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006099:Granuloma / Q000473:pathology*; D014890:Granulomatosis with Polyangiitis / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000378:metabolism*; D016131:Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D018106:CD28 Antigens; D015704:CD4 Antigens; D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma