Abstract
Sézary syndrome (SS) carries a poor prognosis, and infections represent the most frequent cause of death in SS patients. Toll-like receptors (TLRs) are a family of innate immune receptors that induce protective immune responses against infections. We sought to evaluate the ability of TLR agonists to induce inflammatory cytokine, Th2 cytokine, and type I interferon (IFN-I) production by peripheral blood mononuclear cells (PBMC) of untreated SS patients. We detected impaired IL-6, IL-10 and IL-13 secretion by PBMC induced by the agonists for TLR5, TLR3, TLR7 and TLR9 in SS patients, while it was partially recovered by TLR2/TLR4 and TLR7/8 agonists TNF secretion was restored following stimulation with TLR2/TLR4 agonists. IFN-γ was scarcely produced upon TLR activation in SS cells, albeit TLR 7/8 (CL097) enhanced their secretion at lower levels than the control group. TLR9 agonist efficiently induced IFN-I in SS patients, although this positive regulation was not observed for other cytokines, in direct contrast to the broad activity of CL097. Among the TLR agonists, TLR4 was able to induce pro-inflammatory, IL-10 and Th2 secretion, while TLR7-8 agonist induced the inflammatory cytokines, IFN-I and IFN-γ. These findings reveal a dysfunctional cytokine response upon both extracellular and intracellular TLR activation in SS patients, which was partially restored by TLRs agonists.
Highlights
Cutaneous T-cell lymphomas (CTCL), is a non Hodgkin lymphoma that affects skin
The study evaluated the profile of cytokine production by peripheral blood mononuclear cells (PBMC) induced by Toll-like receptors (TLRs) agonists in Sézary syndrome (SS) patients
Studies focusing on pro-inflammatory, Th2, as well as IFN-I production, in SS patients after stimulation with extracellular and intracellular TLR agonists have not been reported previously
Summary
Cutaneous T-cell lymphomas (CTCL), is a non Hodgkin lymphoma that affects skin. Sézary syndrome (SS), is an aggressive CTCL with dissemination of malignant CD4+ T cells with a memory phenotype that can be found in skin, blood, and lymph nodes [1]. A variety of immunologic abnormalities are observed regarding cellmediated immunity in SS patients [2,3], with decreased production of interferon (IFN)-γ (Th1 cytokine), and down-regulated expression of Th1-specific genes, such as TBX21 (T-bet), NKG7, and SCYA5 (RANTES) [2, 4]. Defects in the production of interleukin 12 (IL-12) [3] and increased Th2 cytokines secretion (IL-4, -5, -10, and -13) by the Sézary cell, which can antagonize with Th1 function, have been reported [3,4,5]. SS cells exhibit constitutive STAT3 phosphorylation [67]. The Jak3/STAT pathway promotes the expression of www.impactjournals.com/oncotarget
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