Journal ArticleDOI
T cells maintain an exhausted phenotype after antigen withdrawal and population reexpansion
Daniel T. Utzschneider,Amandine Legat,Silvia A. Fuertes Marraco,Lucie Carrié,Immanuel F. Luescher,Daniel E. Speiser,Dietmar Zehn +6 more
TLDR
It is proposed that during persistent infection, effector T cells stably differentiate into a state that is optimized to limit viral replication without causing overwhelming immunological pathology.Abstract:
During chronic infection, pathogen-specific CD8(+) T cells upregulate expression of molecules such as the inhibitory surface receptor PD-1, have diminished cytokine production and are thought to undergo terminal differentiation into exhausted cells. Here we found that T cells with memory-like properties were generated during chronic infection. After transfer into naive mice, these cells robustly proliferated and controlled a viral infection. The reexpanded T cell populations continued to have the exhausted phenotype they acquired during the chronic infection. Thus, the cells underwent a form of differentiation that was stably transmitted to daughter cells. We therefore propose that during persistent infection, effector T cells stably differentiate into a state that is optimized to limit viral replication without causing overwhelming immunological pathology.read more
Citations
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Journal ArticleDOI
Molecular and cellular insights into T cell exhaustion
E. John Wherry,Makoto Kurachi +1 more
TL;DR: Recent advances that provide a clearer molecular understanding of T cell exhaustion are reviewed and reveal new therapeutic targets for persisting infections and cancer.
Journal ArticleDOI
The diverse functions of the PD1 inhibitory pathway.
TL;DR: The diverse roles of the PD1 pathway in regulating immune responses are discussed and how this knowledge can improve cancer immunotherapy as well as restore and/or maintain tolerance during autoimmunity and transplantation.
Journal ArticleDOI
PD-1 identifies the patient-specific CD8+ tumor-reactive repertoire infiltrating human tumors
Alena Gros,Paul F. Robbins,Xin Yao,Yong F. Li,Simon Turcotte,Eric Tran,John R. Wunderlich,Arnold Mixon,Shawn Farid,Mark E. Dudley,Ken-ichi Hanada,Jorge R. Almeida,Sam Darko,Daniel C. Douek,James Chih-Hsin Yang,Steven A. Rosenberg +15 more
TL;DR: It is demonstrated that PD-1 expression on CD8⁺ TILs also accurately identifies the repertoire of clonally expanded tumor-reactive cells and reveal a dual importance of PD- 1 expression in the tumor microenvironment.
Journal ArticleDOI
Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade
Kristen E. Pauken,Morgan A. Sammons,Pamela M. Odorizzi,Sasikanth Manne,Jernej Godec,Omar Khan,Adam M. Drake,Zeyu Chen,Debattama R. Sen,Makoto Kurachi,R. Anthony Barnitz,Caroline Bartman,Bertram Bengsch,Alexander C. Huang,Jason M. Schenkel,Golnaz Vahedi,W. Nicholas Haining,W. Nicholas Haining,Shelley L. Berger,E. John Wherry +19 more
TL;DR: The data indicate that epigenetic fate inflexibility may limit current immunotherapies, and PD-1 pathway blockade resulted in transcriptional rewiring and reengagement of effector circuitry in the TEX epigenetic landscape.
Journal ArticleDOI
Overcoming T cell exhaustion in infection and cancer.
Kristen E. Pauken,E. John Wherry +1 more
TL;DR: The molecular regulation of T cell exhaustion is reviewed, placing recent findings onPD-1 blockade therapies in cancer in the context of the broader understanding of the roles of the PD-1:PD-L1 pathway in T cell depletion during chronic infection.
References
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Journal ArticleDOI
Two subsets of memory T lymphocytes with distinct homing potentials and effector functions
TL;DR: It is shown that expression of CCR7, a chemokine receptor that controls homing to secondary lymphoid organs, divides human memory T cells into two functionally distinct subsets, which are named central memory (TCM) and effector memory (TEM).
Journal ArticleDOI
Restoring function in exhausted CD8 T cells during chronic viral infection.
Daniel L. Barber,E. John Wherry,David Masopust,Baogong Zhu,James P. Allison,Arlene H. Sharpe,Gordon J. Freeman,Rafi Ahmed +7 more
TL;DR: In this article, the authors analyzed genes expressed in functionally impaired virus-specific CD8 T cells present in mice chronically infected with lymphocytic choriomeningitis virus (LCMV), and compared these with the gene profile of functional memory CD8T cells.
Journal ArticleDOI
T cell exhaustion
TL;DR: Advances in the molecular delineation of T cell exhaustion are clarifying the underlying causes of this state of differentiation and also suggest promising therapeutic opportunities.
Journal Article
Restoring function in exhausted CD8 T cells during chronic viral infection
TL;DR: It is found that even in persistently infected mice that were lacking CD4 T-cell help, blockade of the PD-1/PD-L1 inhibitory pathway had a beneficial effect on the ‘helpless’ CD8 T cells, restoring their ability to undergo proliferation, secrete cytokines, kill infected cells and decrease viral load.
Journal ArticleDOI
PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression
Cheryl L. Day,Daniel Kaufmann,Photini Kiepiela,Julia A. Brown,Eshia Moodley,Sharon Reddy,Elizabeth W Mackey,Joseph D. Miller,Alasdair Leslie,Chantal DePierres,Zenele Mncube,Jaikumar Duraiswamy,Baogong Zhu,Quentin Eichbaum,Marcus Altfeld,E. John Wherry,Hoosen M. Coovadia,Philip J. R. Goulder,Philip J. R. Goulder,Philip J. R. Goulder,Paul Klenerman,Rafi Ahmed,Gordon J. Freeman,Bruce D. Walker,Bruce D. Walker,Bruce D. Walker +25 more
TL;DR: The data indicate that the immunoregulatory PD-1/PD-L1 pathway is operative during a persistent viral infection in humans, and define a reversible defect in HIV-specific T-cell function.