The Identity of Human Tissue-Emigrant CD8+ T Cells

Marcus Buggert; Laura A Vella; Son Nguyen; Vincent H Wu; Zeyu Chen; Takuya Sekine; André Perez-Potti; Colby R Maldini; Sasikanth Manne; Samuel Darko; Amy Ransier; Leticia Kuri-Cervantes; Alberto Sada Japp; Irene Bukh Brody; Martin A Ivarsson; Jean-Baptiste Gorin; Olga Rivera-Ballesteros; Laura Hertwig; Jack P Antel; Matthew E Johnson; Afam Okoye; Louis Picker; Golnaz Vahedi; Ernesto Sparrelid; Sian Llewellyn-Lacey; Emma Gostick; Johan K Sandberg; Niklas Björkström; Amit Bar-Or; Yoav Dori; Ali Naji; David H Canaday; Terri M Laufer; Andrew D Wells; David A Price; Ian Frank; Daniel C Douek; E John Wherry; Maxim G Itkin; Michael R Betts

doi:10.1016/j.cell.2020.11.019

The Identity of Human Tissue-Emigrant CD8⁺ T Cells

Cell. 2020 Dec 23;183(7):1946-1961.e15. doi: 10.1016/j.cell.2020.11.019. Epub 2020 Dec 10.

Authors

Marcus Buggert¹, Laura A Vella², Son Nguyen³, Vincent H Wu³, Zeyu Chen⁴, Takuya Sekine⁵, André Perez-Potti⁵, Colby R Maldini³, Sasikanth Manne⁴, Samuel Darko⁶, Amy Ransier⁷, Leticia Kuri-Cervantes³, Alberto Sada Japp³, Irene Bukh Brody³, Martin A Ivarsson⁵, Jean-Baptiste Gorin⁵, Olga Rivera-Ballesteros⁵, Laura Hertwig⁵, Jack P Antel⁸, Matthew E Johnson⁹, Afam Okoye¹⁰, Louis Picker¹⁰, Golnaz Vahedi¹¹, Ernesto Sparrelid¹², Sian Llewellyn-Lacey¹³, Emma Gostick¹³, Johan K Sandberg⁵, Niklas Björkström⁵, Amit Bar-Or¹⁴, Yoav Dori¹⁵, Ali Naji¹⁶, David H Canaday¹⁷, Terri M Laufer¹⁸, Andrew D Wells¹⁹, David A Price²⁰, Ian Frank²¹, Daniel C Douek⁶, E John Wherry²², Maxim G Itkin²³, Michael R Betts²⁴

Affiliations

¹ Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: [email protected].
² Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Division of Infectious Diseases, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
³ Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁴ Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA.
⁵ Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
⁶ Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
⁷ Genome Analysis Core, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
⁸ Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
⁹ Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹⁰ Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, USA.
¹¹ Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹² Division of Surgery, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
¹³ Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK.
¹⁴ Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, QC, Canada; Center for Neuroinflammation and Experimental Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁵ Division of Cardiology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹⁶ Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁷ Division of Infectious Diseases and HIV Medicine, Case Western Reserve University, Cleveland, OH, USA; Geriatric Research, Education and Clinical Center, Louis Stokes VA Medical Center, Cleveland, OH, USA.
¹⁸ Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Medicine, Corporal Michael J Crescenz VA Medical Center, Philadelphia, PA, USA.
¹⁹ Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
²⁰ Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK; Systems Immunity Research Institute, Cardiff University School of Medicine, Cardiff, UK.
²¹ Division of Infectious Diseases, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²² Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA, USA.
²³ Center for Lymphatic Disorders, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²⁴ Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: [email protected].

Abstract

Lymphocyte migration is essential for adaptive immune surveillance. However, our current understanding of this process is rudimentary, because most human studies have been restricted to immunological analyses of blood and various tissues. To address this knowledge gap, we used an integrated approach to characterize tissue-emigrant lineages in thoracic duct lymph (TDL). The most prevalent immune cells in human and non-human primate efferent lymph were T cells. Cytolytic CD8⁺ T cell subsets with effector-like epigenetic and transcriptional signatures were clonotypically skewed and selectively confined to the intravascular circulation, whereas non-cytolytic CD8⁺ T cell subsets with stem-like epigenetic and transcriptional signatures predominated in tissues and TDL. Moreover, these anatomically distinct gene expression profiles were recapitulated within individual clonotypes, suggesting parallel differentiation programs independent of the expressed antigen receptor. Our collective dataset provides an atlas of the migratory immune system and defines the nature of tissue-emigrant CD8⁺ T cells that recirculate via TDL.

Keywords: CD8; cytotoxic; lymphatic; recirculation; thoracic duct.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
CD8-Positive T-Lymphocytes / cytology*
CD8-Positive T-Lymphocytes / immunology*
Cell Differentiation
Clone Cells
Cytotoxicity, Immunologic
Epigenesis, Genetic
Humans
Immunologic Memory
Lymph Nodes / cytology
Lymph Nodes / immunology
Macaca mulatta
T-Lymphocyte Subsets / immunology
Transcription, Genetic
Transcriptome / genetics

Abstract

Publication types

MeSH terms

Grants and funding