Natural killer cells promote early CD8 T cell responses against cytomegalovirus.
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vor 17 Jahren
Understanding the mechanisms that help promote protective immune
responses to pathogens is a major challenge in biomedical research
and an important goal for the design of innovative therapeutic or
vaccination strategies. While natural killer (NK) cells can
directly contribute to the control of viral replication, whether,
and how, they may help orchestrate global antiviral defense is
largely unknown. To address this question, we took advantage of the
well-defined molecular interactions involved in the recognition of
mouse cytomegalovirus (MCMV) by NK cells. By using congenic or
mutant mice and wild-type versus genetically engineered viruses, we
examined the consequences on antiviral CD8 T cell responses of
specific defects in the ability of the NK cells to control MCMV.
This system allowed us to demonstrate, to our knowledge for the
first time, that NK cells accelerate CD8 T cell responses against a
viral infection in vivo. Moreover, we identify the underlying
mechanism as the ability of NK cells to limit IFN-alpha/beta
production to levels not immunosuppressive to the host. This is
achieved through the early control of cytomegalovirus, which
dramatically reduces the activation of plasmacytoid dendritic cells
(pDCs) for cytokine production, preserves the conventional
dendritic cell (cDC) compartment, and accelerates antiviral CD8 T
cell responses. Conversely, exogenous IFN-alpha administration in
resistant animals ablates cDCs and delays CD8 T cell activation in
the face of NK cell control of viral replication. Collectively, our
data demonstrate that the ability of NK cells to respond very early
to cytomegalovirus infection critically contributes to balance the
intensity of other innate immune responses, which dampens early
immunopathology and promotes optimal initiation of antiviral CD8 T
cell responses. Thus, the extent to which NK cell responses benefit
the host goes beyond their direct antiviral effects and extends to
the prevention of innate cytokine shock and to the promotion of
adaptive immunity.
responses to pathogens is a major challenge in biomedical research
and an important goal for the design of innovative therapeutic or
vaccination strategies. While natural killer (NK) cells can
directly contribute to the control of viral replication, whether,
and how, they may help orchestrate global antiviral defense is
largely unknown. To address this question, we took advantage of the
well-defined molecular interactions involved in the recognition of
mouse cytomegalovirus (MCMV) by NK cells. By using congenic or
mutant mice and wild-type versus genetically engineered viruses, we
examined the consequences on antiviral CD8 T cell responses of
specific defects in the ability of the NK cells to control MCMV.
This system allowed us to demonstrate, to our knowledge for the
first time, that NK cells accelerate CD8 T cell responses against a
viral infection in vivo. Moreover, we identify the underlying
mechanism as the ability of NK cells to limit IFN-alpha/beta
production to levels not immunosuppressive to the host. This is
achieved through the early control of cytomegalovirus, which
dramatically reduces the activation of plasmacytoid dendritic cells
(pDCs) for cytokine production, preserves the conventional
dendritic cell (cDC) compartment, and accelerates antiviral CD8 T
cell responses. Conversely, exogenous IFN-alpha administration in
resistant animals ablates cDCs and delays CD8 T cell activation in
the face of NK cell control of viral replication. Collectively, our
data demonstrate that the ability of NK cells to respond very early
to cytomegalovirus infection critically contributes to balance the
intensity of other innate immune responses, which dampens early
immunopathology and promotes optimal initiation of antiviral CD8 T
cell responses. Thus, the extent to which NK cell responses benefit
the host goes beyond their direct antiviral effects and extends to
the prevention of innate cytokine shock and to the promotion of
adaptive immunity.
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