Immunological memory is characterized by the ability to respond specifically and more rapidly upon a subsequent encounter with a pathogen or antigen. This rapid and specific memory response upon recall is the basis for vaccination. Understanding the mechanisms that regulate immune memory is critical for the rational design of vaccines. We have recently discovered that the intracellular molecule mTOR is a major regulator of memory CD8 T cell differentiation. In vivo administration of rapamycin, a specific inhibitor of mTOR, into mice infected with LCMV significantly enhanced both the quantity and the quality of the virus-specific memory CD8 T cell response. More importantly, we have shown that mTOR acts intrinsically in antigen-specific CD8 T cells to regulate memory differentiation. In this proposal we will investigate the following: 1) role of mTOR-dependent translational control in memory CD8 T cell differentiation;2) determine if autophagy regulates memory CD8 T cell differentiation;3) and investigate if we can harness the mTOR pathway to enhance memory CD8 T cell responses and anti-viral immunity after preventative and therapeutic vaccination. The experiments proposed in this grant should yield new insights into the mechanisms of memory differentiation and provide a framework for the rational design of vaccines that elicit long-term CD8 T cell protective immunity. )

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. We have found that mTORC1 regulates memory CD8 T cell development but the molecular mechanism remains unresolved. Uncovering the mechanism will not only give us a better understanding of memory T cell development but also for establishing a new and more specific molecular target for vaccine development.)

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-IDM-P (02))
Program Officer
Park, Eun-Chung
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Emory University
Schools of Medicine
United States
Zip Code
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
Kamphorst, Alice O; Araki, Koichi; Ahmed, Rafi (2015) Beyond adjuvants: immunomodulation strategies to enhance T cell immunity. Vaccine 33 Suppl 2:B21-8
Lee, Junghwa; Ahn, Eunseon; Kissick, Haydn T et al. (2015) Reinvigorating Exhausted T Cells by Blockade of the PD-1 Pathway. For Immunopathol Dis Therap 6:7-17

Showing the most recent 10 out of 202 publications