Soluble CD40 ligand contributes to dendritic cell-mediated T-cell dysfunction in HIV-1 infection

Abstract

OBJECTIVE Plasma soluble CD40L (sCD40L) is increased during human immunodeficiency virus-1 (HIV) infection, but it is unknown whether it circulates in monomeric or multimeric forms, and whether the circulating forms have differential effects on myeloid dendritic cell (DC) function and adaptive regulation. DESIGN sCD40L forms were measured in plasma samples from HIV-infected donors. The effects of sCD40L forms on DC function were measured in vitro. METHODS To delineate which forms of sCD40L are present in plasma from HIV-infected donors, immunoblots were performed following enrichment of plasma for medium and low abundance proteins. DCs from seronegative donors were exposed to multiple forms of sCD40L prior to Toll-like receptor (TLR) stimulation and DC function and adaptive regulation was assessed in vitro. RESULTS Monomeric and multimeric forms of sCD40L were identified in plasma from ART-treated HIV-infected donors. Though monomeric and multimeric forms of sCD40L had differential effects on DC activation when given alone, both strongly suppressed secretion of the Th1 skewing cytokine, IL-12, upon subsequent TLR stimulation. Furthermore, DCs exposed to both monomeric and multimeric sCD40L induced regulatory T cell formation and T cell anergy. CONCLUSIONS Elevated sCD40L during HIV infection impairs DC function, contributing to innate and adaptive immune dysfunction. Antiretroviral adjunctive therapies that decrease sCD40L may provide immune modulatory benefits.

The plasma levels of soluble ST2 as a marker of gut mucosal damage in early HIV infection

“…We found a positive correlation between plasma sST2 levels and the Kyn/Trp ratio, which suggests that immune activation may be induced by metabolites generated either by gut microbes and/or by IFNγ following systemic viral infection [ 52 , 53 ]. We have previously shown that IDO activity is mediated by sCD40L [ 54 ], another marker of immune activation expressed by activated T cells [ 55 ] and a strong inducer of B cells and antigen presenting cells [ 56 ]. Among different markers of inflammation assessed herein, we observed a strong correlation of sST2 levels with sCD40L in EHI.…”

Potential predictive role of chemotherapy-induced changes of soluble CD40 ligand in untreated advanced pancreatic ductal adenocarcinoma

“…If we consider these results and the crucial role of sCD40L in cancer microenvironment, this biomarker could be useful in a stromal tumor such as PDAC, not forgetting that CA19.9 is negative in ~20% of PDAC patients, 24 as found in six of our patients.…”

“…In vitro and in vivo studies display a crucial involvement of the CD40 pathway in regulating the immune reaction and fibrosis in PDAC, a tumor with a strong interaction between cancer cells and microenvironment. 24 The clinical significance of serum sCD40L as a potential diagnostic and prognostic biomarker in patients with PDAC has been recently reported. 17 Chung and Lim demonstrated that the serum sCD40L levels were significantly increased in the PDAC group compared with the healthy and chronic pancreatitis groups.…”

Evaluation of Different Parameters of Humoral and Cellular Immune Responses in HIV Serodiscordant Heterosexual Couples: Humoral Response Potentially Implicated in Modulating Transmission Rates

“…Despite being infected and contrary to C, HIV + -P had sCD40L levels comparable to HD. Others have reported that sCD40L may impair dendritic cell functionality during HIV infection ( Miller et al, 2015 ). Thus, our result would indicate that HIV + -P would be protected from this phenomenon.…”