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Blood, 1 January 2005, Vol. 105, No. 1, pp. 219-225.
Prepublished online as a Blood First Edition Paper on August 17, 2004; DOI 10.1182/blood-2004-03-1055.
 Previous Article | Next Article 
Submitted March 23, 2004
Accepted July 15, 2004
Impaired CD40L signaling is a cause of defective IL-12 and TNF- production in Sezary syndrome: circumvention by hexameric soluble CD40L
Lars E French*, Bertrand Huard, Maria Wysocka, Ryan Shane, Emmanuel Contassot, Jean-Francois Arrighi, Vincent Piguet, Silvio Calderara, and Alain H Rook
Louis-Jeantet Skin Cancer Laboratory, Geneva University Medical School, Geneva, Switzerland; Department of Dermatology, Geneva University Medical School, Geneva, Switzerland
Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
Department of Dermatology, Geneva University Medical School, Geneva, Switzerland
Apotech Corporation, Epalinges, Switzerland
* Corresponding author; email: lars.french{at}medecine.unige.ch.
Sezary syndrome (SzS) is an advanced form of cutaneous T-cell lymphoma characterized by peripheral blood involvement, impaired cell-mediated immunity and TH1 cytokine production. To understand the mechanism of these defects, we studied the expression and function of CD40L in peripheral blood mononuclear cells (PBMC) of SzS patients. We found that PBMC of SzS patients have a defect in IL-12 and TNF- 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, as IL12 production by anti-CD3 stimulated PBMC was dependent on CD40L in normal donors. The observed defect in tumor cell CD40L expression appears to be due to inappropriate T cell signaling upon CD3 ligation, as 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 PBMC to appropriately produce IL-12 and TNF- could be restored by recombinant hexameric CD40L. Taken together, our results demonstrate that impaired IL-12 and TNF- production in SzS is associated with defective CD4+ T lymphocyte CD40L induction, and indicate that CD40L may have therapeutic potential in SzS.
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