The combination of 4-1BBL and CD40L strongly enhances the capacity of dendritic cells to stimulate HIV-specific T cell responses.

One of the consequences of HIV infection is a progressive loss of T cell functions, resulting in decreased cytokine secretion and proliferation and an increased sensitivity to apoptosis. Therefore, successful therapeutic vaccination approaches should aim at restoring the functionality of existing HIV-specific T cells, as well as to efficiently induce potent, HIV-specific T cells from naïve T cells. In this study, we wanted to determine the stimulatory capacity of DCs coelectroporated with mRNA encoding for different costimulatory molecules of the TNFSF, together with HIV antigen-encoding mRNA. We show that DCs electroporated with 4-1BBL can enhance the proliferation, functionality, cytokine production, and survival of HIV-specific CD8(+) T cells. Furthermore, we are the first to show that a combination of 4-1BBL and CD40L overexpression on DCs dramatically enhances CD4(+) and CD8(+) T cell responses. Finally, we demonstrate that signaling through 4-1BB, but not through CD40, can alleviate the suppressive effect of Tregs on CD8(+) T cell proliferation. Thus, the combination of 4-1BBL and CD40L enhances HIV-specific CD8(+) T cell responses in a synergistic way, resulting in enhanced proliferation of CD4(+) and CD8(+) T cell subsets, an increased cytokine secretion, and a reduced sensitivity to Treg-mediated immune suppression.