Impaired CD40L signaling is a cause of defective IL-12 and TNF-alpha production in Sézary syndrome: circumvention by hexameric soluble CD40L.
Sézary syndrome (SzS) is an advanced form of cutaneous T-cell lymphoma characterized by peripheral blood involvement, impaired cell-mediated immunity, and T-helper 1 (TH1) cytokine production. To understand the mechanism of these defects, we studied the expression and function of CD40L in peripheral blood mononuclear cells (PBMCs) of patients with SzS. We found that PBMCs of patients with SzS have a defect in interleukin-12 (IL-12) and tumor necrosis factor-alpha (TNF-alpha) production upon anti-CD3 stimulation and that tumor CD4+ T lymphocytes have a specific defect in CD40L induction after anti-CD3 ligation in vitro. This defect may explain the poor IL-12 production, because IL-12 production by anti-CD3-stimulated PBMCs was dependent on CD40L in healthy donors. The observed defect in tumor cell CD40L expression appears to be due to inappropriate T-cell signaling upon CD3 ligation, because expression of other T-cell activation antigens such as CD25, and to a lesser extent CD69, are also impaired on tumor cells. Importantly however, the inability of SzS PBMCs to appropriately produce IL-12 and TNF-alpha could be restored by recombinant hexameric CD40L. Taken together, our results demonstrate that impaired IL-12 and TNF-alpha production in SzS is associated with defective CD4+ T lymphocyte CD40L induction and indicate that CD40L may have therapeutic potential in SzS.
French
Lars E
LE
Louis-Jeantet Skin Cancer Center, Department of Dermatology, Geneva University Medical School, Switzerland. lars.french@medecine.unige.ch
Huard
Bertrand
B
Wysocka
Maria
M
Shane
Ryan
R
Contassot
Emmanuel
E
Arrighi
Jean-François
JF
Piguet
Vincent
V
Calderara
Silvio
S
Rook
Alain H
AH
D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D017252:CD3 Complex / Q000378:metabolism; D023201:CD40 Ligand / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D012751:Sezary Syndrome / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D012995:Solubility; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000378:metabolism
D017252:CD3 Complex; D011948:Receptors, Antigen, T-Cell; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand; D018664:Interleukin-12