Granzyme B regulates antigen-specific CD8 cell responses to Sendai virus (168.10)

Abstract

Abstract Introduction. Human regulatory T (T reg) cells express functional granzymes and perforin (Gzm/Prf) and can induce autologous target cell death in vitro. Prf1-/- mice die from exaggerated immune responses after viral challenges, implicating a potential role for this pathway in immune regulation. To further investigate the role of GzmB in immune regulation of viral infections, we infected wild-type (WT) mice, Gzmb-/- mice and Prf1-/- mice with Sendai virus (SeV) and characterized the magnitude of the immune response. Methods. Mice were infected with SeV and Antigen (Ag)-specific CD8 responses were measured by flow cytometry. T reg cell depletion was performed with the anti-CD25 mAb PC61. Results. Gzmb-/- mice exhibited a significant increase in the number of Ag-specific CD8 cells in the lungs and draining lymph nodes in response to SeV infection. This increase was not the result of failure in viral clearance since viral titers in Gzmb-/- mice were similar to WT mice and significantly less than Prf1-/- mice. T reg cells from WT mice expressed high levels of GzmB, and depletion of T reg cells from these mice resulted in an increase in the number of Ag-specific CD8 cells, similar to that observed in Gzmb-/- mice. Furthermore, Gzmb-/- T reg cells displayed a clear defect in their ability to suppress CD8 cell proliferation in vitro. Conclusion. Taken together, these results suggest a possible role for GzmB in the T reg cell compartment in immune regulation of viral infections.