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TREG CHARACTERIZATION IN NORMAL AND SIV - INFECTED NON-HUMAN PRIMATES

TREG CHARACTERIZATION IN NORMAL AND SIV - INFECTED NON-HUMAN PRIMATES. Background Tregs suppress T-cell activation and proliferation in vitro and in vivo in both mice and humans.

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TREG CHARACTERIZATION IN NORMAL AND SIV - INFECTED NON-HUMAN PRIMATES

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  1. TREG CHARACTERIZATION IN NORMAL AND SIV-INFECTED NON-HUMAN PRIMATES

  2. Background • Tregs suppress T-cell activation and proliferation in vitro and in vivo in both mice and humans. • These cells have been shown to inhibit various autoimmune diseases, induce tolerance to alloantigens, prevent inappropriate Th2 responses to environmental allergens and are able to confer protection against airway and intestinal inflammation in mice. • Tregs may be responsible for collateral damage due to excessive suppression of immune responses against parasites and tumor cells. • T regulatory cells were initially defined as CD4+CD25+ T cells. FoxP3 is currently the most specific marker of Tregs.

  3. FOX-P3 is expressed mainly by CD4+ T cells in both Rh and AGMs Real-time PCR

  4. FOX-P3 is exclusively expressed by CD3+CD4+CD25+T cells CD3+CD4+T cells FOX-P3 Expression 8% FOX-P3 AGM FOX-P3 FOX-P3 6% AGM Rh Semiquantitative PCR for FOX-P3 in normal Rh and normal AGMs Peripheral blood Rh CD25

  5. Failure to phenotype the Tregs in simian models

  6. Tregs inhibit proliferation of conventional T cells in non-human primates Proliferation of CD4+CD25neg T cells in the presence of CD4+CD25+ T cells Ratio 1:1 Proliferation of CD4+CD25neg T cells in the absence of CD4+CD25+ T cells Inhibition is dose dependent

  7. Treg identification in tissues in non-human primates

  8. Study of Treg Dynamics During SIV Infection of Rh and AGMs

  9. Chronic immune activation and rapid turnover of T cells are hallmarks of pathogenic infections (role for Tregs?). • In contrast to pathogenic infections, AGMs rarely develop AIDS and show no significant increase in immune activation and turnover of T cells during SIV infection. • Comparison between Rh and AGM models would be useful for the study of Tregs.

  10. High Number of Tregs Relative to Low Numbers of CD4+ T Cells in AGMs

  11. Dynamics of Tregs in SIVmac-Infected Rh Foxp3 gene expression in PBMC from SIVmac251-infected Rh (necropsy) % CD4+CD25+

  12. Dynamics of Tregs in SIVagm-Infected AGMs

  13. Delayed Anti-Inflammatory Reaction in SIVmac Infection During the Primary Infection Rh TGFb1 gene expression (PBMCs) IL-10 gene expression (PBMCs) AGMs

  14. Different Dynamics of Tregs in LN in SIVmac-Infected Rh and SIVagm-Infected AGMs (1) The number of Tregs in LN in SIVmac-infected Rh

  15. Different Dynamics of Tregs in LN in SIVmac-Infected Rh and SIVagm-Infected AGMs (2)

  16. Intestinal Tregs in SIVmac and SIVagm-infected monkeys SIVagm primary infection

  17. Conclusions • Fully functionalTregs are present in both Rh and AGMs. • Our studysuggest some possible differences in Tregs between pathogenic and non-pathogenic models for SIV. A higher proportion of CD4 T cells express FoxP3 in AGMs than in Rh in the intestine Generation of Tregs in SIVagm infected AGMs preceeds the increase in this T cell subset in SIVmac-infected macaques. This may protect the natural host from mounting an inappropriate immune response The Tregs are better preserved in chronic SIVagm infection, which may explain the lack of chronic immune activation in non- pathogenic models.

  18. Acknowledgements Pasteur Institute Paris TNPRC Pandrea Lab M. Pattison C. Quave C. Coleman Apetrei Lab R. Gautam N. Katz C. Monjure C. Carter Vet Med R. Bohm J. Dufour R. Veazey A. Lackner M. Muller-Trutwin M. J.-Y. Ploquin F. Barre-Sinoussi Cochin Institute, University Paris 5 C. Butor School of Medicine, Tulane University W. Zou I. Kryczeck T. Curiel Supported by NIH grants to IP and CA

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