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The gene regulatory basis of bystander activation in CD8 + T cells

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Watson, Neva B., Patel, Ravi K., Kean, Connor, Veazey, Janelle, Oyesola, Oyebola O., Laniewski, Nathan, Grenier, Jennifer K., Wang, Jocelyn +12 more·2024·Science Immunology
DOI 10.1126/sciimmunol.adf8776PMC PMC11973513
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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.

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  • IL-23 produced by keratinocytes can activate skin-resident IL-17+ γδT cells to control bacterial and fungal pathogen infections.

    “it was previously reported that IL-23 produced by keratinocytes can activate skin-resident IL-17+ γδT cells to control bacterial and fungal pathogen infections.32,33”

    From Skin-resident T cells play an important role in controlling skin colonization of Candidozyma (Candida) auris (2026) · cites this paper as [32]

    The Discussion (page unavailable) says that subsets of neonatal γδ T cells secrete IL-17 upon activation, and reference 45 identifies a study in which IL-23 induces IL-17 production from γδ T cells. Our copy does not say that keratinocytes produce the IL-23, that the cells are skin-resident, or that this pathway controls bacterial and fungal infections. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • All skin-resident T cells are pre-activated T cells with effector/memory-like phenotypes, which could be activated in an innate fashion by alterations of molecular cues of the local tissue they reside in.

    “All skin-resident T cells are pre-activated T cells with effector/memory-like phenotypes, which could be activated in an innate fashion by alterations of molecular cues of the local tissue they reside in.26,27,28,29,30,31,32”

    From Skin-resident T cells play an important role in controlling skin colonization of Candidozyma (Candida) auris (2026) · cites this paper as [32]

    The Introduction (page not provided) describes neonatal CD8+ T cells as effector-like before stimulation and able to respond to innate cytokines; it also describes inflammation-dependent, TCR-independent activation in a subset of naïve CD8+ T cells. The paper does not establish that all skin-resident T cells are pre-activated or that changes in local skin-tissue cues activate them. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Authors
Watson, N. B., Patel, R. K., Kean, C., Veazey, J., Oyesola, O. O., Laniewski, N., Grenier, J. K., Wang, J., Tabilas, C., Yee Mon, K. J., McNairn, A. J., Peng, S. A., Wesnak, S. P., Nzingha, K., Davenport, M. P., Tait Wojno, E. D., Scheible, K. M., Smith, N. L., Grimson, A., & Rudd, B. D.
Affiliations
  • Cornell University (US)
  • University of Washington (US)
  • University of Rochester Medicine (US)
  • Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA.
  • University of Pennsylvania (US)
  • UNSW Sydney (AU)
  • Department of Immunology, University of Washington, Seattle, WA 98109, USA.
Corresponding author
  • Watson, Neva B.
  • Patel, Ravi K.
  • Kean, Connor
  • Grimson, Andrew
  • Rudd, Brian D.
ORCID
Venue
Science Immunology
Publisher
American Association for the Advancement of Science (AAAS)
Published
2024-02-23
Volume
9
Issue
92
Pages
eadf8776-eadf8776
ISSN
2470-9468 (ISSN-L)
DOI
10.1126/sciimmunol.adf8776
PMC
PMC11973513
OpenAlex
W4392094135
Cited by
46
References
6
Citations by year
2026: 18 · 2025: 18 · 2024: 10
FWCI
7.69
Type
journal article
Language
en
Open access
Locations
  • Science Immunology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • UNSWorks (University of New South Wales, Sydney, Australia) (submittedVersion, cc-by)
Funders
  • University of Rochester
  • Medical Center, University of Rochester
  • National Health and Medical Research Council (1173027)
  • National Institute of Allergy and Infectious Diseases (K08AI108870, R01AI110613, R01AI105265, U01AI131348, R21AI138025, R01AI130379, HHSN272201200005C)
  • Fogarty International Center
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK134410)
  • National Institute of Child Health and Human Development
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD076210)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
Keywords
bystander activation, CD8+ T cells, neonatal T cells, innate cytokines, chromatin remodeling, enhancers, transcription factors, innate-like T cells, innate-adaptive immune interface, T cell differentiation, multi-omics
MeSH terms
Adult, Animals, Antigens, Humans, Immunity, Innate, T-Lymphocyte Subsets, Cytokines, CD8-Positive T-Lymphocytes, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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