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Joseph Conrad Kalams Laboratory Microbiology and Immunology Vanderbilt University

PD-1 expression is increased on dominant T-cell clonotypes within epitope-specific T-cell populations in chronic HIV infection. Joseph Conrad Kalams Laboratory Microbiology and Immunology Vanderbilt University Nashville, TN USA. TCR. HIV peptide. MHC-I. Clements, Curr Opp Str Bio, 2006.

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Joseph Conrad Kalams Laboratory Microbiology and Immunology Vanderbilt University

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  1. PD-1 expression is increased on dominant T-cell clonotypes within epitope-specific T-cell populations in chronic HIV infection Joseph Conrad Kalams Laboratory Microbiology and Immunology Vanderbilt University Nashville, TN USA

  2. TCR HIV peptide MHC-I Clements, Curr Opp Str Bio, 2006. HIV-specific T-cells Recognize Peptides from Viral Proteins • Infected cells process viral peptides and presented them in complex with surface MHC molecules • Killing of infected cells by epitope-specific CTL is mediated by contacts between the T-cell receptor (TCR) and p:MHC complex • Acute Infection = control • Chronic Infection = exhaustion

  3. CD4CD8 HIV-specific CTL HIV-specific CTL HIV-specific CTL CD8 Tetramer PD-1 Tetramer PD-1 PD-1 Expression in HIV Infection • PD-1 is a co-stimulatory molecule which inhibits antigen-receptor signaling on lymphocytes • PD-1 is upregulated and highly expressed on T-cell populations in HIV+ subjects, especially epitope-specific CTL • Despite expressing high levels of PD-1, epitope-specific CTL expand in vitro in response to stimulation with cognate antigen • We investigated PD-1 expression on 27 epitope-specific responses in 17 therapy naïve subjects with varying degrees of viral control (mean, 14000 HIV-RNA copies/ml; range, 50-100000)

  4. HIV-specific CTL have More PD-1 High Cells than CD4 or CD8 Populations % PD-1 High CD4 – 54% CD8 – 63% PD-1 High PD-1 KF11 – 78% PD-1 High n = 17 subjects; 27 epitopes Epitope-specific CTL express high levels of PD-1 PD-1

  5. PD-1 Expression on Epitope-specific Clonotypes • We are evaluating the role of the T-cell receptor (TCR) repertoire in the recognition of viral epitopes • Through sequence analysis of TCR V-beta (TRBV) CDR3 region, we know that epitope-specific responses are comprised of oligo-clonal expansions of CTL

  6. HIV-specific CTL Tetramer PD-1 PD-1 Expression on Epitope-specific Clonotypes • We are evaluating the role of the T-cell receptor (TCR) repertoire in the recognition of viral epitopes • Sequence analysis of TCR V-beta (TRBV) CDR3 region, we know that epitope-specific responses are comprised of oligo-clonal expansions of CTL • Dominant clonotype with various sub-dominant clonotypes • Epitope-specific clonotypic populations are identified and tracked by co-staining with MHC-I tetramer and TRBV-specific antibodies

  7. PD-1 Dominant TRBV Populations Have More PD-1 % High Cells than Sub-Dominant TRBV Populations % PD-1 High TRBV PD-1 DomTRBV – 84% Non-TRBV – 69% PD-1 High n = 17 subjects; 27 epitopes 6 tetramers, 1-5 tetramers/subject Sub-dominant clonotypes express lower levels of PD-1 than dominant clonotypes

  8. CFSE Assessing Functional Differences in Clonotypic Populations Epitope-specific clonotypes were sorted, labeled with CFSE, and stimulated with cognate peptide in the presence of autologous APCs Dominant TRBV Sub-Dominant TRBV CD8

  9. Sub-Dominant TRBV Dominant TRBV CD8 13.1% 38.3% CFSE CFSE IFN-gamma IFN-gamma Sub-dominant Clonotypes Produce Higher Levels of Interferon-gamma than Dominant Clonotypes Interferon-gamma production was measured on CFSE+ CTL Dominant TRBV Sub-Dominant TRBV CFSE

  10. Sub-dominant Clonotypes Produce Higher Levels of Interferon-gamma than Dominant Clonotypes Sub-dominant clonotypes produce more IFN-gamma

  11. Summary • PD-1 is more highly expressed on epitope-specific CTL than on CD4 or CD8 populations • PD-1 is more highly expressed on dominant clonotypes than on sub-dominant clonotypes within epitope-specific responses • Sub-dominant, PD-1 low clonotypes produce higher levels of interferon-gamma by percentage and magnitude when compared to dominant, PD-1 high clonotypes • Data Not Shown – Dominant clonotypes display marked survival and proliferation defects in the absence of or in low levels of stimulation

  12. Conclusions • PD-1 is more highly expressed on epitope-specific CTL than on CD4 or CD8 populations • PD-1 is more highly expressed on dominant clonotypes than on sub-dominant clonotypes within epitope-specific responses • Sub-dominant, PD-1 low clonotypes produce higher levels of interferon-gamma by percentage and magnitude when compared to dominant, PD-1 high clonotypes • Data Not Shown – Dominant clonotypes display marked survival and proliferation defects in the absence of or in low levels of stimulation • PD-1 is likely upregulated on dominant circulating clonotypes as a result of constant immune surveillance and subsequent antigen-induced activation • Sub-dominant clonotypes represent a potential reservoir of relatively functional CTL capable of responding to antigen stimulation

  13. Acknowledgements Study Cohort and Volunteers Kalams Lab Current Spyros Kalams Brenna Simons* Louise Barnett Shelly Lorey Ramesh Ramalingam Lakshmi Sadagopal Rita Smith Jie Wei Former Amanda Antons Dirk Meyer-Olson Scott Vancompernolle D’Aquila Lab Lorraine Sutton Michael Vetter Vanderbilt-Meharry CFAR Flow Cytometry Core Sequencing Facility Grant Support HIV/AIDS Research Training Program (HARTP) 1 T32I060571

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