慢性疾患における機能低下した免疫細胞の細胞レベルの傷

 There are a lot of persons who exercise daily. Such persons well-understand self-condition, in which they avoid the physical over-burden. If the physical burden exceeds their tolerability, strong “fatigue” remains after exercise. In this way, all physical system includes fatigue against the exercise condition. This fatigue exists in a cell level. In our body, immune system functions as watch dog against threat including virus, toxic materials, inflammatory signal and cancer. This immune system also has fatigue when its burden is excess, which is generally called “Exhausted immune cell”. Exhausted immune cell loses some important functions as immune system such as cytotoxicity (killer T cell). When chronic burden including cancer and virus exists in the body, immune system must always continue to function/work against chronic lesion, which leads “over-work/exhaustion”. SARS-CoV-2 infection is not exception. Exhausted makers including PD1, TIM3, LAG3, CTLA4, NKG2A and CD39 have confirmed in the patient with severe symptom(5). Here, we have one question. If SARS-CoV-2 virus is excluded and the patient is recovered, is exhausted immune cell also recovered? Kathleen B. Yates et al, Pierre Tonnerre et al, and Mohamed S. Abdel-Hakeem et al. indicated one finding in which exhausted immune cell includes epigenetic “scarring”(1-3). When we imagine “scarring”, we call to mind “skin scarring” firstly like Ref.(4) Figure.1. In the skin, scaring may be alleviated or diminished by the down-regulation of 1 En1-lineage-positive fibroblasts which causes fibrotic tissues(4). In immune cell, epigenetic landscape is changed as indicated in Ref.(2) Fig.2b. How immune cell epigenetically changes is dependent on antigen including Hepatitis C virus, Cytomegalovirus, EpsteinBarr virus and Influenza (2). However, expressed gene of immune cell is changed in common after chronic infection. This epigenetic change is associated with open chromatin region, which has high dynamics(3)(Ref.(6) See Fig.1). This fact may be applied to immune cell against chronic cancer. Therefore, the immune cell of the patient with cancer after complete remission could be changed genetically. From this hypothesis, when the cancer treatment become prolonged, immune function is weakened and immunotherapy becomes hard to be effective. In the case where the burden of treatment against cancer is large, we need to provide treatment through some routes including surgical resection, chemotherapy, radiotherapy, metabolic therapy, hyperthermia and the other type or/and diverse type immunotherapy. We need to alleviate the immune burden against refractory tumor. Cannot to mention about effective concrete analysis method, but it may be valuable to confirm whether such epigenetic scarring after chronic burden against immune cells emerges “in whole body” including blood vessel or not. If there are deflection in each region of the body (for example, exhausted immune cell is significantly larger population near the lesion), we may be able to promote engraftment of “no-scarring” immune cell including autogenous transplantation and circulating promotion (ex. mild exercise). Apart from the cost problem, but we could take advantage of the cell-specific delivery system, in which we deliver “non-scarring” stem T cell with the surface decoration specific to the cancer lesion in order to make tissue-specific engraftment. On the other hand, long-term genetic change may need to be observe after epigenetic scarring, meaning cell-level wound healing model. However, Pierre Tonnerre, David Wolski, Sonu Subudhi et al. show the no-improvement so that immune cell can be activated up to 3 years after treatment(2), but this result may change by metabolic condition in the environment including cell nutrition, because retain rate of scarred cell is 77.1% after 1 years, not 100%(Ref.(1) See Fig.6c). We may need to provide medical intervention for the immune cell for the patients taken the long-term treatment.
 We need to accept many physical destinies including accidental diseases through my life. Even mild bone fracture leave (small degree of) permanent scarring. High degree of recovery from tissue damage, that is wound healing, is one of the most difficult challenges in the medicine. These studies(1-3) makes us reconsider about this unavoidable assignment including single cell-level in the future medical development.
 
(Reference)
(1)
Kathleen B. Yates, Pierre Tonnerre, Genevieve E. Martin, Ulrike Gerdemann, Rose Al Abosy, Dawn E. Comstock, Sarah A. Weiss, David Wolski, Damien C. Tully, Raymond T. Chung, Todd M. Allen, Arthur Y. Kim, Sarah Fidler, Julie Fox, John Frater, Georg M. Lauer, W. Nicholas Haining & Debattama R. Sen
Epigenetic scars of CD8+ T cell exhaustion persist after cure of chronic infection in humans
Nature Immunology volume 22, pages1020–1029 (2021)
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Author information
Author notes
These authors contributed equally: W. Nicholas Haining, Debattama R. Sen.
Affiliations
Department of Pediatric Oncology, Dana–Farber Cancer Institute, Boston, MA, USA
Kathleen B. Yates, Ulrike Gerdemann, Rose Al Abosy, Dawn E. Comstock, Sarah A. Weiss, W. Nicholas Haining & Debattama R. Sen
Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA
Kathleen B. Yates & Debattama R. Sen
Broad Institute of MIT and Harvard, Cambridge, MA, USA
Kathleen B. Yates
Division of Gastroenterology, Liver Center, Massachusetts General Hospital, Boston, MA, USA
Pierre Tonnerre, David Wolski, Raymond T. Chung & Georg M. Lauer
Inserm U976, Institut de Recherche Saint-Louis, Paris, France
Pierre Tonnerre
Nuffield Department of Medicine, University of Oxford, Oxford, UK
Genevieve E. Martin & John Frater
Department of Infectious Diseases, Central Clinical School, Monash University, Melbourne, Australia
Genevieve E. Martin
Division of Medical Sciences, Harvard Medical School, Boston, MA, USA
Dawn E. Comstock & Sarah A. Weiss
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
Damien C. Tully & Todd M. Allen
Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
Damien C. Tully
Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA, USA
Arthur Y. Kim
Division of Medicine, Wright Fleming Institute, Imperial College, London, UK
Sarah Fidler
Imperial College National Institute for Health Research Biomedical Research Centre, London, UK
Sarah Fidler
Department of Genitourinary Medicine and Infectious Disease, Guy’s and St Thomas’ NHS Foundation Trust, London, UK
Julie Fox
King’s College National Institute for Health Research Biomedical Research Centre, London, UK
Julie Fox
Oxford National Institute for Health Research Biomedical Research Centre, Oxford, UK
John Frater
Merck Research Laboratories, Boston, MA, USA
W. Nicholas Haining
(2)
Pierre Tonnerre, David Wolski, Sonu Subudhi, Jihad Aljabban, Ruben C. Hoogeveen, Marcos Damasio, Hannah K. Drescher, Lea M. Bartsch, Damien C. Tully, Debattama R. Sen, David J. Bean, Joelle Brown, Almudena Torres-Cornejo, Maxwell Robidoux, Daniel Kvistad, Nadia Alatrakchi, Ang Cui, David Lieb, James A. Cheney, Jenna Gustafson, Lia L. Lewis-Ximenez, Lucile Massenet-Regad, Thomas Eisenhaure, Jasneet Aneja, W. Nicholas Haining, Raymond T. Chung, Nir Hacohen, Todd M. Allen, Arthur Y. Kim & Georg M. Lauer
Differentiation of exhausted CD8+ T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory
Nature Immunology volume 22, pages1030–1041 (2021)
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Author information
Affiliations
Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
Pierre Tonnerre, David Wolski, Sonu Subudhi, Jihad Aljabban, Ruben C. Hoogeveen, Marcos Damasio, Hannah K. Drescher, Lea M. Bartsch, Joelle Brown, Almudena Torres-Cornejo, Maxwell Robidoux, Daniel Kvistad, Nadia Alatrakchi, James A. Cheney, Jenna Gustafson, Jasneet Aneja, Raymond T. Chung & Georg M. Lauer
Inserm U976, Université de Paris, Institut de Recherche Saint-Louis, Paris, France
Pierre Tonnerre & Lucile Massenet-Regad
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
Damien C. Tully, David J. Bean & Todd M. Allen
Division of Medical Sciences, Harvard Medical School, Boston, MA, USA
Debattama R. Sen & W. Nicholas Haining
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
Debattama R. Sen & W. Nicholas Haining
Broad Institute of MIT and Harvard, Cambridge, MA, USA
Ang Cui, David Lieb, Thomas Eisenhaure & Nir Hacohen
Harvard-MIT Division of Health Sciences and Technology, MIT, Cambridge, MA, USA
Ang Cui
Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
Lia L. Lewis-Ximenez
Division of Infectious Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
Jasneet Aneja & Arthur Y. Kim
Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA
Nir Hacohen
(3)
Mohamed S. Abdel-Hakeem, Sasikanth Manne, Jean-Christophe Beltra, Erietta Stelekati, Zeyu Chen, Kito Nzingha, Mohammed-Alkhatim Ali, John L. Johnson, Josephine R. Giles, Divij Mathew, Allison R. Greenplate, Golnaz Vahedi & E. John Wherry
Epigenetic scarring of exhausted T cells hinders memory differentiation upon eliminating chronic antigenic stimulation
Nature Immunology volume 22, pages1008–1019 (2021)
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Author information
Author notes
Erietta Stelekati
Present address: Department of Microbiology and Immunology, University of Miami, Miami, FL, USA
Affiliations
Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA
Mohamed S. Abdel-Hakeem, Sasikanth Manne, Jean-Christophe Beltra, Erietta Stelekati, Zeyu Chen, Kito Nzingha, Mohammed-Alkhatim Ali, Josephine R. Giles, Divij Mathew, Allison R. Greenplate & E. John Wherry
Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Mohamed S. Abdel-Hakeem, Sasikanth Manne, Jean-Christophe Beltra, Erietta Stelekati, Zeyu Chen, Kito Nzingha, Mohammed-Alkhatim Ali, John L. Johnson, Josephine R. Giles, Divij Mathew, Allison R. Greenplate, Golnaz Vahedi & E. John Wherry
Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
Mohamed S. Abdel-Hakeem
Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA
Jean-Christophe Beltra, Josephine R. Giles & E. John Wherry
Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA
John L. Johnson
Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA
Golnaz Vahedi
Penn Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA
Golnaz Vahedi
(4)
Richard A.F. Clark, M.D.
To Scar or Not to Scar
The New England Journal of Medicine 2021; 385:469-47
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From the Departments of Dermatology and Biomedical Engineering, State University of New York at Stony Brook Health Sciences Center, Stony Brook, NY.
(5)
Zeyu Chen & E. John Wherry
T cell responses in patients with COVID-19
Nature Reviews Immunology volume 20, pages529–536 (2020)
(6)
Sandy L. Klemm, Zohar Shipony & William J. Greenleaf
Chromatin accessibility and the regulatory epigenome
Nature Reviews Genetics volume 20, pages207–220 (2019)