Temporary CXCR3 and CCR5 Antagonism Following Vaccination Enhances Memory CD8 T Cell Immune Responses

Abstract

Abstract Although current vaccination strategies have been successful at preventing a variety of human diseases, attempts at vaccinating against some pathogens such as AIDS and tuberculosis (TB) have been more problematic, largely because abnormally high numbers of antigen-specific CD8 + T cells are required for protection. This study assessed the effect on host immune response of temporarily dampening the chemokine receptors CXCR3 and CCR5 after vaccination by administration of TAK-779, a small-molecule CXCR3 and CCR5 antagonist commonly used to inhibit HIV infection. Our results showed that use of TAK-779 enhanced memory CD8 + T cell immune responses both qualitatively and quantitatively. Treatment with TAK-779 following vaccination of an influenza virus antigen resulted in enhanced memory generation, with more CD8 + CD127 + memory precursors and fewer terminally differentiated effector CD8 + CD69 + T cells. These memory T cells were able to become IFN-γ-secreting effector cells when re-encountering the same antigen, which can further enhance the efficacy of vaccination. The mice vaccinated in the presence of TAK-779 were better protected upon influenza virus challenge than the controls. These results show that vaccination, while temporarily inhibiting chemokine receptors CXCR3 and CCR5 by TAK-779, could be a promising strategy to generate large numbers of protective memory CD8 + T cells.