Programmed death-1 (PD-1) appears transiently on the surface of T cells following immune activation and is highly expressed in T cells chronically exposed to antigen. While PD-1 likely plays an important role in governing responses to self antigen, there is compelling evidence that PD-1-mediated inhibitory signals also play a central role in the functional exhaustion of T cells during chronic viral infection. This has been demonstrated in several animal and human viral infections including HIV. Most notably, antibody blockade between PD-1 and its ligands results in reactivation of the """"""""exhausted"""""""" antigen-specific T cells. This effect has been demonstrated in a number of persistent viral infections, including those from HIV in humans and in the mouse with lymphocytic choriomenigitis virus (LCMV). These data strongly suggest that PD-1 is more than just a marker of T cell exhaustion but rather a critical mediator of this phenotype. These data also imply that manipulating PD-1 expression, signaling, and/or function could lead to novel immune based therapies to treat chronic infection. Surprisingly, virtually nothing is known about the regulation of PD-1 gene expression at the molecular level ? this basic tenet of PD-1 biology and immunology will be elucidated in this proposal. Our preliminary data provide evidence that PD-1 Is regulated at multiple levels. Using comparative genomics, DNasel hypersensitivity assays, gene reporter assays, and bisulfite sequence, we have identified regions in both mouse and human genomes that are likely to be involved in the regulation of PD-1 and have correlated two of these regions with transcriptional activity. We have also found evidence that the PD-1 gene is differentially methylated in viral-specific CDS T cells in vivo, suggesting a role for epigenetic control of the gene. Experiments in this application will identify the cis-acting elements, Aim 1;determine the breadth and dynamics of epigenetic mechanisms, Aim 2;and identify transcription factors that are associated with PD-1 gene regulation, Aim 3. In all of the aims we will begin with model cell lines, confirm and verify that information in primary mouse and human CDS T cells, test the validity .of these findings in antigen-specific CDS T cell following LCMV infection;and examine HIV-specific CDS T cells to determine how PD-1 regulation factors into HIV disease progression. These approaches will provide molecular targets for pathways that may be ultimately used for treating HIV disease, chronic infection, autoimmunity and aiding to transplantation success.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI080192-05
Application #
8380108
Study Section
Special Emphasis Panel (ZAI1-PRJ-A)
Project Start
Project End
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
5
Fiscal Year
2012
Total Cost
$385,737
Indirect Cost
$47,177
Name
Emory University
Department
Type
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Wieland, Andreas; Kamphorst, Alice O; Adsay, N Volkan et al. (2018) T cell receptor sequencing of activated CD8 T cells in the blood identifies tumor-infiltrating clones that expand after PD-1 therapy and radiation in a melanoma patient. Cancer Immunol Immunother 67:1767-1776
Youngblood, Ben; Hale, J Scott; Kissick, Haydn T et al. (2017) Effector CD8 T cells dedifferentiate into long-lived memory cells. Nature 552:404-409
Kamphorst, Alice O; Wieland, Andreas; Nasti, Tahseen et al. (2017) Rescue of exhausted CD8 T cells by PD-1-targeted therapies is CD28-dependent. Science 355:1423-1427
Bally, Alexander P R; Tang, Yan; Lee, Joshua T et al. (2017) Conserved Region C Functions To Regulate PD-1 Expression and Subsequent CD8 T Cell Memory. J Immunol 198:205-217
Im, Se Jin; Hashimoto, Masao; Gerner, Michael Y et al. (2016) Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature 537:417-421
Kamphorst, Alice O; Araki, Koichi; Ahmed, Rafi (2015) Beyond adjuvants: immunomodulation strategies to enhance T cell immunity. Vaccine 33 Suppl 2:B21-8
Chetty, Shivan; Govender, Pamla; Zupkosky, Jennifer et al. (2015) Co-infection with Mycobacterium tuberculosis impairs HIV-Specific CD8+ and CD4+ T cell functionality. PLoS One 10:e0118654
Porichis, Filippos; Hart, Meghan G; Zupkosky, Jennifer et al. (2014) Differential impact of PD-1 and/or interleukin-10 blockade on HIV-1-specific CD4 T cell and antigen-presenting cell functions. J Virol 88:2508-18
Penaloza-MacMaster, Pablo; Kamphorst, Alice O; Wieland, Andreas et al. (2014) Interplay between regulatory T cells and PD-1 in modulating T cell exhaustion and viral control during chronic LCMV infection. J Exp Med 211:1905-18
Xiao, Yanping; Yu, Sanhong; Zhu, Baogong et al. (2014) RGMb is a novel binding partner for PD-L2 and its engagement with PD-L2 promotes respiratory tolerance. J Exp Med 211:943-59

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