CD8(+) Treg cells suppress CD8(+) T cell-responses by IL-10-dependent mechanism during H5N1 influenza virus infection

Although Treg-cell-mediated suppression during infection or autoimmunity has been described, functions of Treg cells during highly pathogenic avian influenza virus infection remain poorly characterized. Here we found that in Foxp3-GFP transgenic mice, CD8(+) Foxp3(+) Treg cells, but not CD4(+) Foxp3(+) Treg cells, were remarkably induced during H5N1 infection. In addition to expressing CD25, the CD8(+) Foxp3(+) Treg cells showed a high level of GITR and produced IL-10. In an adoptive transfer model, CD8(+) Treg cells suppressed CD8(+) T-cell responses and promoted H5N1 virus infection, resulting in enhanced mortality and increased virus load in the lung. Furthermore, in vitro neutralization of IL-10 and studies with IL-10R-deficient mice in vitro and in vivo demonstrated an important role for IL-10 production in the capacity of CD8(+) Treg cells to inhibit CD8(+) T-cell responses. Our findings identify a previously unrecognized role of CD8(+) Treg cells in the negative regulation of CD8(+) T-cell responses and suggest that modulation of CD8(+) Treg cells may be a therapeutic strategy to control H5N1 viral infection.