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...

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Published in:	Nature immunology Vol. 22; no. 8; pp. 1030 - 1041
Main Authors:	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.
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01.08.2021 Nature Publishing Group
Subjects:	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
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Abstract	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.
AbstractList	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. 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. 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.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. 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. 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 towards 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, T cell stimulation duration impacts exhaustion recovery, with antigen removal after long-term exhaustion being insufficient for development of functional T cell memory.
Author	Torres-Cornejo, Almudena Subudhi, Sonu Bean, David J. Robidoux, Maxwell Alatrakchi, Nadia Bartsch, Lea M. Cheney, James A. Lauer, Georg M. Hoogeveen, Ruben C. Allen, Todd M. Haining, W. Nicholas Tonnerre, Pierre Damasio, Marcos Sen, Debattama R. Kim, Arthur Y. Cui, Ang Aneja, Jasneet Chung, Raymond T. Hacohen, Nir Aljabban, Jihad Eisenhaure, Thomas Brown, Joelle Massenet-Regad, Lucile Gustafson, Jenna Wolski, David Lieb, David Tully, Damien C. Kvistad, Daniel Lewis-Ximenez, Lia L. Drescher, Hannah K.
AuthorAffiliation	2 Inserm U976, Université de Paris, Institut de Recherche Saint-Louis, Paris, France 3 Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA 10 Division of Infectious Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA 6 Broad Institute of MIT and Harvard, Cambridge, MA, USA 8 Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil 7 Harvard-MIT Division of Health Sciences and Technology, MIT, Cambridge, MA, USA 5 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA 4 Division of Medical Sciences, Harvard Medical School, Boston, MA, USA 1 Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA 9 Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA
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BackLink	https://www.ncbi.nlm.nih.gov/pubmed/34312544$$D View this record in MEDLINE/PubMed
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Copyright	The Author(s), under exclusive licence to Springer Nature America, Inc. 2021 2021. The Author(s), under exclusive licence to Springer Nature America, Inc. The Author(s), under exclusive licence to Springer Nature America, Inc. 2021.
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Notes	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.
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PublicationTitle	Nature immunology
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Publisher	Nature Publishing Group US Nature Publishing Group
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Snippet	T cell exhaustion is associated with failure to clear chronic infections and malignant cells. Defining the molecular mechanisms of T cell exhaustion and...
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SubjectTerms	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
Title	Differentiation of exhausted CD8+ T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory
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