IFN-α boosts epitope cross-presentation by dendritic cells via modulation of proteasome activity.

We have investigated the molecular mechanisms underlying the peculiar cross-presentation efficiency of human dendritic cells (DCs) differentiated from monocytes in the presence of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) and Interferon (IFN)-α (IFN-DCs). To this end, we evaluated the capability of IFN-DCs to present and cross-present epitopes derived from Epstein-Barr Virus (EBV) or human melanoma-associated antigens after exposure to cell lysates or apoptotic cells. In an autologous setting, IFN-DCs loaded with Lymphoblastoid Cell Lines (LCL) lysates or apoptotic LCL were highly efficient in expanding, respectively, EBV-specific class II- or class I-restricted memory T cell responses.

Identification of new HIV-1 Gag-specific cytotoxic T lymphocyte responses in BALB/c mice.

Background: As HIV-specific cytotoxic T cells play a key role during acute and chronic HIV-1 infection in humans, the ability of potential anti-HIV vaccines to elicit strong, broad T cell responses is likely to be crucial. The HIV-1 Gag antigen is widely considered a relevant antigen for the development of an anti-HIV vaccine since it is one of the most conserved viral proteins and is also known to induce T cell responses. In the majority of studies reporting Gag-specific cellular immune responses induced by Gag-based vaccines, only a small number of Gag T cell epitopes were tested in preclinical mouse models, thus giving an incomplete picture of the numerous possible cellular immune responses against this antigen.

The Tat protein broadens T cell responses directed to the HIV-1 antigens Gag and Env: implications for the design of new vaccination strategies against AIDS.

We have previously shown that the biologically active Tat protein targets and efficiently enters dendritic cells, and increases the proteolytic activities of the immunoproteasome, thereby favoring the generation and presentation of the subdominant MHC-I binding CTL epitopes of heterologous antigens. In the present study, we demonstrate that Tat broadens in vivo epitope-specific T cell responses directed to heterologous antigens including HIV structural proteins. Specifically, co-immunization of mice with OVA and Tat proteins induces CTL responses against subdominant and cryptic OVA-derived epitopes, which are not detected in mice vaccinated with OVA alone.

Peptidyl vinyl ester derivatives: new class of selective inhibitors of proteasome trypsin-like activity.

The proteasome is a multicatalytic proteinase complex which plays a central role in intracellular protein degradation. We report here the synthesis and biological activities of a new class of specific proteasome inhibitors selective for trypsin-like activity. These tripeptide-based compounds bearing a C-terminal vinyl ester are nontoxic, and do not affect cell proliferation, but are able to modulate the generation and presentation of immunogenic peptides presented by MHC class I molecules.