Caspase-8 restricts antiviral CD8 T cell hyperaccumulation.

Abstract

The magnitude of CD8 T cell responses against viruses is checked by the balance of proliferation and death. Caspase-8 (CASP8) has the potential to influence response characteristics through initiation of apoptosis, suppression of necroptosis, and modulation of cell death-independent signal transduction. Mice deficient in CASP8 and RIPK3 (<i>Casp8</i>^<i>-/-</i><i>Ripk3</i>^<i>-/-</i> ) mount enhanced peak CD8 T cell levels against the natural mouse pathogen murine cytomegalovirus (MCMV) or the human pathogen herpes simplex virus-1 compared with littermate control RIPK3-deficient or WT C57BL/6 mice, suggesting an impact of CASP8 on the magnitude of antiviral CD8 T cell expansion and not on contraction. The higher peak response to MCMV in <i>Casp8</i>^<i>-/-</i><i>Ripk3</i>^<i>-/-</i> mice resulted from accumulation of greater numbers of terminally differentiated KLRG1^hi effector CD8 T cell subsets. Antiviral <i>Casp8</i>^<i>-/-</i><i>Ripk3</i>^<i>-/-</i> T cells exhibited enhanced proliferation when splenocytes were transferred into WT recipient mice. Thus, cell-autonomous CASP8 normally restricts CD8 T cell proliferation following T cell receptor activation in response to foreign antigen. Memory inflation is a hallmark quality of the T cell response to cytomegalovirus infection. Surprisingly, MCMV-specific memory inflation was not sustained long-term in <i>Casp8</i>^<i>-/-</i><i>Ripk3</i>^<i>-/-</i> mice even though these mice retained immunity to secondary challenge. In addition, the accumulation of abnormal B220⁺CD3⁺ T cells in these viable CASP8-deficient mice was reduced by chronic MCMV infection. Combined, these data brings to light the cell death-independent role of CASP8 during CD8 T cell expansion in mice lacking the confounding impact of RIPK3-mediated necroptosis.