Watson et al. investigated “bystander activation”, in which T cells are activated by cytokines rather than TCR stimulation. Single-cell transcriptomics and chromatin accessibility profiling revealed that neonatal CD8+ T cells were more functionally diverse and more susceptible to IL-12- and IL-18-induced chromatin remodeling that opened up numerous AP-1 binding sites, enabling innate-like effector responses to non-specific pathogens. Most adult CD8+ T cells were less capable of such cytokine-induced chromatin remodeling, and instead expressed more Bach2, which blocks AP-1 binding. However, some innate-like CD8+ T cells could still be identified in both mice and patients into adulthood.
Contributed by Lauren Hitchings
ABSTRACT: CD8(+) T cells are classically recognized as adaptive lymphocytes based on their ability to recognize specific foreign antigens and mount memory responses. However, recent studies indicate that some antigen-inexperienced CD8(+) T cells can respond to innate cytokines alone in the absence of cognate T cell receptor stimulation, a phenomenon referred to as bystander activation. Here, we demonstrate that neonatal CD8(+) T cells undergo a robust and diverse program of bystander activation, which corresponds to enhanced innate-like protection against unrelated pathogens. Using a multi-omics approach, we found that the ability of neonatal CD8(+) T cells to respond to innate cytokines derives from their capacity to undergo rapid chromatin remodeling, resulting in the usage of a distinct set of enhancers and transcription factors typically found in innate-like T cells. We observed that the switch between innate and adaptive functions in the CD8(+) T cell compartment is mediated by changes in the abundance of distinct subsets of cells. The innate CD8(+) T cell subset that predominates in early life was also present in adult mice and humans. Our findings provide support for the layered immune hypothesis and indicate that the CD8(+) T cell compartment is more functionally diverse than previously thought.
Author Info: (1) Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA. (2) Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, US
Author Info: (1) Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA. (2) Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA. (3) Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA. (4) Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA. (5) Department of Immunology, University of Washington, Seattle, WA 98109, USA. (6) David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA. (7) Genomics Innovation Hub and TREx Facility, Institute of Biotechnology, Cornell University, Ithaca, NY 14853, USA. (8) Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA. (9) Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA. (10) Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA. (11) Genomics Innovation Hub and TREx Facility, Institute of Biotechnology, Cornell University, Ithaca, NY 14853, USA. (12) Department of Clinical Science, Cornell University, Ithaca, NY 14853, USA. (13) Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA. (14) Institute for Immunology, University of Pennsylvania, Philadelphia, PA 19104, USA. (15) Kirby Institute for Infection and Immunity, UNSW Australia, Sydney, NSW 2052, Australia. (16) Department of Immunology, University of Washington, Seattle, WA 98109, USA. (17) Department of Pediatrics, University of Rochester, Rochester, NY 14642, USA. (18) Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA. (19) Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA. (20) Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA.
