Chronic viral infections are characterized by a state of T cell dysfunction that is associated with expression of the PD-1 (programmed cell death 1) inhibitory receptor. A better understanding of the mechanisms that regulate CD8 T cell responses during chronic viral infection is required to improve immunotherapies that restore function in exhausted CD8 T cells. We have recently identified a novel population of virus specific CD8 T cells that act as stem cells to maintain T cell responses during chronic infection of mice with lymphocytic choriomeningitis virus (LCMV). These stem-like LCMV specific CD8 T cells are found in the lymphoid tissues where they reside predominantly in the T cell zones along with nave CD8 T cells. They act as stem cells by undergoing a slow self-renewal and can also differentiate to give rise to the terminally differentiated CD8 T cells that are found at the major sites of infection in lymphoid as well as non-lymphoid tissues. Most importantly, the proliferative burst of T cells that is seen after PD-1 blockade comes almost exclusively from this stem-like CD8 T cell subset. Our studies have been confirmed and extended by others who have found similar CD8 T cells in other chronic viral infections of mice and also in chronic infections of non-human primates and humans. The studies proposed in the application are now focused on understanding how these virus specific stem-like CD8 T cells are generated and maintained during chronic infection and how this information can be used to develop rational approaches for optimizing PD-1 directed immunotherapy. The following specific aims are proposed to achieve these goals:
Specific aim 1 : To understand how the generation and maintenance of virus specific stem-like CD8 T cells is regulated during chronic viral infection.
Specific aim 2 : To develop strategies for enhancing virus specific stem-like CD8 T cells and optimizing PD-1 directed immunotherapy.

Public Health Relevance

Memory CD8 T cells are an essential component of protective immunity, and generating effective memory CD8 T cell populations with large quantity and superior quality is a major goal of successful vaccines against chronic viral infections. Uncovering the mechanisms that give us a better understanding of the memory T cell populations during chronic viral infection could lead to establishing new and more specific molecular targets for vaccine development and chronic viral control. !

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI030048-28
Application #
10107735
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Dupuy, Lesley Conrad
Project Start
1990-07-01
Project End
2023-02-28
Budget Start
2021-03-01
Budget End
2022-02-28
Support Year
28
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Emory University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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
Lee, Junghwa; Hashimoto, Masao; Im, Se Jin et al. (2017) Adenovirus Serotype 5 Vaccination Results in Suboptimal CD4 T Helper 1 Responses in Mice. J Virol 91:
Ye, Lilin; Lee, Junghwa; Xu, Lifan et al. (2017) mTOR Promotes Antiviral Humoral Immunity by Differentially Regulating CD4 Helper T Cell and B Cell Responses. J Virol 91:
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
Furuta, Yousuke; Komeno, Takashi; Nakamura, Takaaki (2017) Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proc Jpn Acad Ser B Phys Biol Sci 93:449-463
Araki, Koichi; Morita, Masahiro; Bederman, Annelise G et al. (2017) Translation is actively regulated during the differentiation of CD8+ effector T cells. Nat Immunol 18:1046-1057
Ahn, Eunseon; Youngblood, Ben; Lee, Junghwa et al. (2016) Demethylation of the PD-1 Promoter Is Imprinted during the Effector Phase of CD8 T Cell Exhaustion. J Virol 90:8934-46
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
Wu, Tuoqi; Wieland, Andreas; Lee, Judong et al. (2015) Cutting Edge: miR-17-92 Is Required for Both CD4 Th1 and T Follicular Helper Cell Responses during Viral Infection. J Immunol 195:2515-9
Zhu, Chen; Sakuishi, Kaori; Xiao, Sheng et al. (2015) An IL-27/NFIL3 signalling axis drives Tim-3 and IL-10 expression and T-cell dysfunction. Nat Commun 6:6072

Showing the most recent 10 out of 202 publications