Impact of regulatory T cells on immune responses to SIV
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Transcript of Impact of regulatory T cells on immune responses to SIV
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Impact of regulatory T cells on immune responses to SIV
SIVmac251
Macaques with few T-regs
Macaques with many T-regs
Follow T cell responses,
activation, and disease outcome
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Chronic immune activation and HIV disease progression
• Among untreated patients, T cell activation is strongly associated with clinical progression to AIDS
• On therapy, T cell activation is associated with decreased CD4+ T cell gains
• Mechanisms that may underly these associations:– Depletion of the naïve T cell pool– Proliferation and loss of effector-memory T cells– Interference with T cell production in bone marrow and
thymus– Increased replication of virus within T cells
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Immune control of SIV
• Appearance of SIV-specific CD8+ T cells is
coincident with decline of viral load from peak
• CD8-depleted macaques do not reduce viral
load relative to peak
• Specific MHC-I alleles are associated with
slow disease progression
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Impact of regulatory T cells on immune responses to SIV
SIVmac251
Adult macaques with 4% T-regs
Infant macaques with 8% T-regs
Follow T cell responses,
activation, and disease outcome
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Hypothesis: In the setting of SIV infection, regulatory T cells will control immune activation
and thereby slow disease progression
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CD25 CD25
Infant macaque T-regs are CD25+CD127lowC
D12
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FO
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Add CD25 1:3
CFSE
CD25-depletedAll cells Add CD25 1:3CD25-depletedAll cells
Infant macaque T-regs are CD25+CD127low
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Infant macaques have more T-regs in peripheral blood
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Infant macaques have more T-regs in peripheral blood
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Infant macaques have more T-regs in lymph node tissue
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Infant macaque T-regs are more highly suppressive in vitro
Uninfected
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Impact of regulatory T cells on immune responses to SIV
SIVmac251
Adult macaques with 4% T-regs
Infant macaques with 8% T-regs
Follow T cell responses,
activation, and disease outcome
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Disease progression in adult and infant macaques
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CD8+ T cell responses to SIV
IFN
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Adult—all cells
Infant—CD25-depleted
Adult—CD25-depletedInfant—all cells
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SIV-specific CD4+ T cell proliferation is suppressed by T-regs
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SE
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SIV-specific CD4+ T cells are suppressed by T-regs
IFN
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Adult—CD25-depletedInfant—all cells
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Widespread T cell activation is not suppressed by infant macaque T-regs
Infant CD4
Adult CD8
Infant CD8
Adult CD4
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Conclusions
• Infant macaques have more regulatory T cells in peripheral blood and tissues
• Infant T-regs are more highly functional in vitro
• After infection with SIV, most infants had high viral loads and rapid disease progression
• Infected infants displayed weak and transient SIV-specific T cell responses
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Conclusions
• T-regs in the infant but not the adult directly suppressed SIV-specific CD4 responses
• In infants and adults, T-regs were not able to directly suppress SIV-specific CD8 responses
• In infants and adults, T-regs had no apparent effect on T cell activation
• These observations suggest that the T-reg compartment of the infant macaque facilitates rapid disease progression
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Acknowledgements
• Paul Baum
• David Favre
• Juliet Easlick
• Joseph Moore
Abel LaboratoryMcCune Laboratory
• Marta Marthas
• Koen van Rompay
UC Davis