Caspase-8 restricts antiviral CD8 T cell hyperaccumulation

Author:

Feng, Yanjun  Daley-Bauer, Lisa P.  Roback, Linda  Guo, Hongyan  Koehler, Heather S.  Potempa, Marc  Lanier, Lewis L.  Mocarski, Edward S.  

Journal:

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Issue Date:

2019

Abstract(summary):

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 (Casp8(-/-)Ripk3(-/)(-)) 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 Casp8(-/)(-)Ripk3(-/-) mice resulted from accumulation of greater numbers of terminally differentiated KLRG1(hi) effector CD8 T cell subsets. Antiviral Casp8(-)(/-)Ripk3(-)(/-) 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 Casp8(-/-)Ripk3(-/)(-) 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.

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