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Impact of regulatory T cells on immune responses to SIV

Impact of regulatory T cells on immune responses to SIV. Macaques with few T-regs. Follow T cell responses, activation, and disease outcome. SIVmac251. Macaques with many T-regs. Chronic immune activation and HIV disease progression.

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Impact of regulatory T cells on immune responses to SIV

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  1. Impact of regulatory T cells on immune responses to SIV Macaques with few T-regs Follow T cell responses, activation, and disease outcome SIVmac251 Macaques with many T-regs

  2. 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

  3. 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

  4. Impact of regulatory T cells on immune responses to SIV Adult macaques with 4% T-regs Follow T cell responses, activation, and disease outcome SIVmac251 Infant macaques with 8% T-regs

  5. Hypothesis: In the setting of SIV infection, regulatory T cells will control immune activation and thereby slow disease progression

  6. Infant macaque T-regs are CD25+CD127low CD127 FOXP3

  7. Infant macaque T-regs are CD25+CD127low All cells CD25-depleted Add CD25 1:3

  8. CD25+CD127low,% of CD3+CD4+ 1 wk 3 wks 5 wks 4-5 yrs 18-30 mos Infant macaques have more T-regs in peripheral blood

  9. Infant macaques have more T-regs in peripheral blood % CD25+ % CD25+CD127low % CD25+FOXP3+ % CD25+ per µL

  10. Infant macaques have more T-regs in lymph node tissue Adult Infant FOXP3+, % of CD4+ Node

  11. *p < 0.0001 Division index,% of Conrol 1:3 T-regs:Responders Infected Infant macaque T-regs are more highly suppressive in vitro Adult Division index,% of Conrol Infant T-regs:Responders Uninfected

  12. Impact of regulatory T cells on immune responses to SIV Adult macaques with 4% T-regs Follow T cell responses, activation, and disease outcome SIVmac251 Infant macaques with 8% T-regs

  13. Disease progression in adult and infant macaques log10(vRNA) Adult Infant Weeks post-infection

  14. CD8+ T cell responses to SIV Adult—all cells Adult Adult—CD25-depleted Infant Infant—all cells Infant—CD25-depleted IFN-g+TNF-a+, % of CD8 IFN-g+TNF-a+, % of CD8

  15. Adult—all cells Adult—CD25-depleted Infant—all cells Infant—CD25-depleted CFSEdim, % of CD4+ SIV-specific CD4+ T cell proliferation is suppressed by T-regs Adult Infant CFSEdim, % of CD4+

  16. SIV-specific CD4+ T cells are suppressed by T-regs Adult—all cells Adult Adult—CD25-depleted Infant Infant—all cells Infant—CD25-depleted IFN-g+IL-2+, % of CD4 IFN-g+IL-2+, % of CD4

  17. Widespread T cell activation is not suppressed by infant macaque T-regs Infant CD4 Infant CD8 Adult CD4 Adult CD8

  18. 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

  19. Conclusions • T-regs in the infant but not the adult directly suppressed SIV-specific CD4responses • 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

  20. Acknowledgements Abel Laboratory McCune Laboratory • Paul Baum • David Favre • Juliet Easlick • Joseph Moore UC Davis • Marta Marthas • Koen van Rompay

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