Differentiation of exhausted CD8+ T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory

T cell exhaustion is associated with failure to clear chronic infections and malignant cells. Defining the molecular mechanisms of T cell exhaustion and reinvigoration is essential to improving immunotherapeutic modalities. Here we confirmed pervasive phenotypic, functional and transcriptional diffe...

Celý popis

Uložené v:
Podrobná bibliografia
Vydané v:Nature immunology Ročník 22; číslo 8; s. 1030 - 1041
Hlavní autori: Tonnerre, Pierre, Wolski, David, Subudhi, Sonu, Aljabban, Jihad, Hoogeveen, Ruben C., Damasio, Marcos, Drescher, Hannah K., Bartsch, Lea M., Tully, Damien C., Sen, Debattama R., Bean, David J., Brown, Joelle, Torres-Cornejo, Almudena, Robidoux, Maxwell, Kvistad, Daniel, Alatrakchi, Nadia, Cui, Ang, Lieb, David, Cheney, James A., Gustafson, Jenna, Lewis-Ximenez, Lia L., Massenet-Regad, Lucile, Eisenhaure, Thomas, Aneja, Jasneet, Haining, W. Nicholas, Chung, Raymond T., Hacohen, Nir, Allen, Todd M., Kim, Arthur Y., Lauer, Georg M.
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: New York Nature Publishing Group US 01.08.2021
Nature Publishing Group
Predmet:
631/250/2152/1566/1571
631/250/2152/1566/2493
631/250/2502/248
631/250/255/2514
692/699/255/234/2513/1551
Antigens
Antiviral Agents - therapeutic use
Biomedical and Life Sciences
Biomedicine
CD8 antigen
CD8-Positive T-Lymphocytes - immunology
CD8-Positive T-Lymphocytes - pathology
Cell differentiation
Cell Differentiation - immunology
Chronic infection
Epitopes - genetics
Hepacivirus - immunology
Hepatitis
Hepatitis C
Hepatitis C, Chronic - drug therapy
Hepatitis C, Chronic - immunology
Humans
Immunologic Memory - immunology
Immunological memory
Immunology
Infections
Infectious Diseases
Lymphocytes
Lymphocytes T
Memory cells
Molecular modelling
Phenotype
Transcription
ISSN:1529-2908, 1529-2916, 1529-2916
On-line prístup:Získať plný text
Tagy: Pridať tag
Žiadne tagy, Buďte prvý, kto otaguje tento záznam!
Popis
Shrnutí:T cell exhaustion is associated with failure to clear chronic infections and malignant cells. Defining the molecular mechanisms of T cell exhaustion and reinvigoration is essential to improving immunotherapeutic modalities. Here we confirmed pervasive phenotypic, functional and transcriptional differences between memory and exhausted antigen-specific CD8 + T cells in human hepatitis C virus (HCV) infection before and after treatment. After viral cure, phenotypic changes in clonally stable exhausted T cell populations suggested differentiation toward a memory-like profile. However, functionally, the cells showed little improvement, and critical transcriptional regulators remained in the exhaustion state. Notably, T cells from chronic HCV infection that were exposed to antigen for less time because of viral escape mutations were functionally and transcriptionally more similar to memory T cells from spontaneously resolved HCV infection. Thus, the duration of T cell stimulation impacts exhaustion recovery, with antigen removal after long-term exhaustion being insufficient for the development of functional T cell memory. Lauer and colleagues examine CD8 + T cells following cure of human hepatitis C virus (HCV) infection. CD8 + T cells exposed to chronic HCV-specific activation show durable functional, phenotypic and transcriptional exhaustion that is maintained even after antigen stimulus is removed.
Bibliografia:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 14
content type line 23
T.M.A. designed and supervised the viral sequencing study.
G.M.L., N.H., and W.N.H. supervised RNAseq experiments and data analysis.
D.W., S.S., D.L., and D.R.S. analyzed RNAseq data.
P.T., S.S., D.S., and G.M.L. drafted the manuscript with the help of all other authors.
P.T., D.W., J.A.J., R.C.H., M.D., H.D., L.B., D.C.T., D.J. B., A.T.C., M.R., D.K., N.A., A.C., J.A.C., L.M., and T.E. performed and analyzed experiments.
P.T., D.W., and G.M.L. conceived and designed the experiments.
J.B., J.G., L.L.L., and J.A. contributed to the clinical cohort recruitment and clinical database management.
AUTHOR CONTRIBUTIONS
R.T.C., A.Y.K., and G.M.L. designed the clinical trial and patient selection.
ISSN:1529-2908
1529-2916
1529-2916
DOI:10.1038/s41590-021-00982-6