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

Objective: Plasma soluble CD40 ligand (sCD40L) is increased during HIV-1 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 function and adaptive regulation. Design: sCD40L forms were measured in plasma samples from HIV-infected donors. The effects of sCD40L forms on dendritic cell 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. Dendritic cells from seronegative donors were exposed to multiple forms of sCD40L prior to Toll-like receptor stimulation and dendritic cell function and adaptive regulation was assessed in vitro. Results: Monomeric and multimeric forms of sCD40L were identified in plasma from antiretroviral therapy-treated HIV-infected donors. Although monomeric and multimeric forms of sCD40L had differential effects on dendritic cell activation when given alone, both strongly suppressed secretion of the Th1 skewing cytokine, interleukin-12, upon subsequent Toll-like receptor stimulation. Furthermore, dendritic cells exposed to both monomeric and multimeric sCD40L induced regulatory T-cell formation and T-cell anergy. Conclusion: Elevated sCD40L during HIV infection impairs dendritic cell function, contributing to innate and adaptive immune dysfunction. Antiretroviral adjunctive therapies that decrease sCD40L may provide immune modulatory benefits.