Fate mapping reveals the age structure of the peripheral T cell compartment

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 10; pp. 3974 - 3981
• Main Authors: Reynaldi, Arnold, Smith, Norah L., Schlub, Timothy E., Tabilas, Cybelle, Venturi, Vanessa, Rudd, Brian D., Davenport, Miles P.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 05-03-2019
• Series: PNAS Plus
• Subjects: Age; Age composition; Aging - genetics; Aging - immunology; Animal models; Animals; Biological Sciences; CD8 antigen; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; Cell fate; Decay; Decay rate; Fate maps; Hematopoietic stem cells; Immune system; Infections; Life span; Lymphocytes; Lymphocytes T; Mapping; Mathematical models; Mice; Mice, Transgenic; Models, Immunological; Ontogeny; Physical Sciences; PNAS Plus; Stem cell transplantation; Stem cells; mathematical modeling; CD8+ T cells; immunology; ontogeny; T cell homeostasis
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1811634116

Accumulating evidence indicates that the immune system does not develop in a linear fashion, but rather as distinct developmental layers formed from sequential waves of hematopoietic stem cells, each giving rise to unique populations of immune cells at different stages of development. Although recent studies have indicated that conventional CD8⁺ T cells produced in early life persist into adulthood and exhibit distinct roles during infection, the developmental architecture of the peripheral T cell compartment remains undefined. In this study, we used a mouse model to permanently label CD8⁺ T cells produced during distinct windows of development and traced their history to generate fate maps of CD8⁺ T cells produced during different stages of life. We then used mathematical modeling to understand the age structure of the CD8⁺ T cell compartment across the lifespan. Interestingly, we found that survival rate of CD8⁺ T cells depends on both the age and developmental origin of the cells. Recently produced cells show an initial rapid decay rate, which slows with age of the animal at which the cells were produced. For cells produced at any age, the rate of decay also slows with the age of the cell. We derive a function to describe this and predict the “age distribution” of the CD8⁺ T cell pool for animals of any given age. These data provide a quantitative framework for understanding the ontogeny of the CD8⁺ T cell compartment and help to contextualize age-related changes in the CD8⁺ T cell response to infection.