A Crucial Role for Infected-Cell/Antibody Immune Complexes in the Enhancement of Endogenous Antiviral Immunity by Short Passive Immunotherapy

PLoS Pathogens

Henri-Alexandre Michaud¹  Javier Hernandez¹  Kevin Thiolon¹  Mireia Pelegrin²  Chantal Jacquet²  Laurent Gros²  Roudaina Nasser³  Marc Piechaczyk³  Tiphanie Gomard³ 

[1] Institut de Génétique Moléculaire de Montpellier, UMR 5535 CNRS, Montpellier, France;Université Montpellier 1, Montpellier, France;Université Montpellier 2, Montpellier, France

关键词: Cytotoxic T cells;    T cells;    Immune response;    Antibodies;    Flow cytometry;    Antiviral immune response;    Antibody response;    Cell-mediated immunity;   

DOI  :  10.1371/journal.ppat.1000948

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Antiviral monoclonal antibodies (mAbs) represent promising therapeutics. However, most mAbs-based immunotherapies conducted so far have only considered the blunting of viral propagation and not other possible therapeutic effects independent of virus neutralization, namely the modulation of the endogenous immune response. As induction of long-term antiviral immunity still remains a paramount challenge for treating chronic infections, we have asked here whether neutralizing mAbs can, in addition to blunting viral propagation, exert immunomodulatory effects with protective outcomes. Supporting this idea, we report here that mice infected with the FrCasE murine retrovirus on day 8 after birth die of leukemia within 4–5 months and mount a non-protective immune response, whereas those rapidly subjected to short immunotherapy with a neutralizing mAb survive healthy and mount a long-lasting protective antiviral immunity with strong humoral and cellular immune responses. Interestingly, the administered mAb mediates lysis of infected cells through an antibody-dependent cell cytotoxicity (ADCC) mechanism. In addition, it forms immune complexes (ICs) with infected cells that enhance antiviral CTL responses through FcγR-mediated binding to dendritic cells (DCs). Importantly, the endogenous antiviral antibodies generated in mAb-treated mice also display the same properties, allowing containment of viral propagation and enhancement of memory cellular responses after disappearance of the administered mAb. Thus, our data demonstrate that neutralizing antiviral mAbs can act as immunomodulatory agents capable of stimulating a protective immunity lasting long after the end of the treatment. They also show an important role of infected-cells/antibody complexes in the induction and the maintenance of protective immunity through enhancement of both primary and memory antiviral T-cell responses. They also indicate that targeting infected cells, and not just viruses, by antibodies can be crucial for elicitation of efficient, long-lasting antiviral T-cell responses. This must be considered when designing antiviral mAb-based immunotherapies.

【 授权许可】

CC BY