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Development and function of specified thymic iNKT1 cells critically depend on an Ets1-Tbet transcription factor axis

Morgan, Roy C. ; Frank, Cameron ; Li, Lu ; Moos, Ezra ; Attaway, Mary ; Melanson, Randy A. ; Gioulbasani, Marianthi ; Li, Sophia ; Bolonduro, Olubusayo and Koh, Andrew , et al. (2026) In Journal of immunology (Baltimore, Md. : 1950) 215(3).
Abstract

Invariant natural killer T 1 (iNKT1) cells are prototypic interferon γ-producing, innate-like T lymphocytes that play crucial roles in protection against pathogen infection and cancer. In the thymus, where these cells develop, iNKT cells contribute to the recruitment of antigen-presenting cells and promote T cell tolerance. Although the transcriptional programs guiding iNKT cell specification are well characterized, the mechanisms directing their subsequent maturation and tissue-associated effector functions remain poorly understood. Here, we reveal that the transcription factor Ets1 is essential for the maintenance of thymic iNKT1 cells and for their differentiation into a CD103+ transforming growth factor β1-dependent, tissue-resident... (More)

Invariant natural killer T 1 (iNKT1) cells are prototypic interferon γ-producing, innate-like T lymphocytes that play crucial roles in protection against pathogen infection and cancer. In the thymus, where these cells develop, iNKT cells contribute to the recruitment of antigen-presenting cells and promote T cell tolerance. Although the transcriptional programs guiding iNKT cell specification are well characterized, the mechanisms directing their subsequent maturation and tissue-associated effector functions remain poorly understood. Here, we reveal that the transcription factor Ets1 is essential for the maintenance of thymic iNKT1 cells and for their differentiation into a CD103+ transforming growth factor β1-dependent, tissue-resident phenotype, in addition to playing a critical role in maintaining iNKT1 effector function in the liver and spleen. Mechanistically, Ets1 limits the expression of CD8 effector T cell-associated genes and restricts the induction of the transcription factor Tbet. Elevated Tbet expression partially rescues thymic iNKT1 cell numbers in the absence of Ets1 but shifts their differentiation toward a migratory, CD103- pathway. In peripheral tissues, elevated Tbet expression failed to overcome the requirement for Ets1 in activation-induced interferon γ-production but instead drove increased cytotoxic effector protein expression. Our findings establish Ets1 as a central regulator of iNKT1 cell homeostasis, enforcing a tissue-resident identity in the thymus and supporting context-appropriate effector function.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
development, effector function, iNKT cell, transcription
in
Journal of immunology (Baltimore, Md. : 1950)
volume
215
issue
3
publisher
American Association of Immunologists
external identifiers
  • pmid:41847852
  • scopus:105033752073
ISSN
1550-6606
DOI
10.1093/jimmun/vkag024
language
English
LU publication?
yes
id
a660bd40-89da-42fb-a5d9-29e29bc26135
date added to LUP
2026-05-07 14:10:19
date last changed
2026-05-08 03:00:03
@article{a660bd40-89da-42fb-a5d9-29e29bc26135,
  abstract     = {{<p>Invariant natural killer T 1 (iNKT1) cells are prototypic interferon γ-producing, innate-like T lymphocytes that play crucial roles in protection against pathogen infection and cancer. In the thymus, where these cells develop, iNKT cells contribute to the recruitment of antigen-presenting cells and promote T cell tolerance. Although the transcriptional programs guiding iNKT cell specification are well characterized, the mechanisms directing their subsequent maturation and tissue-associated effector functions remain poorly understood. Here, we reveal that the transcription factor Ets1 is essential for the maintenance of thymic iNKT1 cells and for their differentiation into a CD103+ transforming growth factor β1-dependent, tissue-resident phenotype, in addition to playing a critical role in maintaining iNKT1 effector function in the liver and spleen. Mechanistically, Ets1 limits the expression of CD8 effector T cell-associated genes and restricts the induction of the transcription factor Tbet. Elevated Tbet expression partially rescues thymic iNKT1 cell numbers in the absence of Ets1 but shifts their differentiation toward a migratory, CD103- pathway. In peripheral tissues, elevated Tbet expression failed to overcome the requirement for Ets1 in activation-induced interferon γ-production but instead drove increased cytotoxic effector protein expression. Our findings establish Ets1 as a central regulator of iNKT1 cell homeostasis, enforcing a tissue-resident identity in the thymus and supporting context-appropriate effector function.</p>}},
  author       = {{Morgan, Roy C. and Frank, Cameron and Li, Lu and Moos, Ezra and Attaway, Mary and Melanson, Randy A. and Gioulbasani, Marianthi and Li, Sophia and Bolonduro, Olubusayo and Koh, Andrew and Sigvardsson, Mikael and Bartom, Elizabeth T. and Kee, Barbara L.}},
  issn         = {{1550-6606}},
  keywords     = {{development; effector function; iNKT cell; transcription}},
  language     = {{eng}},
  number       = {{3}},
  publisher    = {{American Association of Immunologists}},
  series       = {{Journal of immunology (Baltimore, Md. : 1950)}},
  title        = {{Development and function of specified thymic iNKT1 cells critically depend on an Ets1-Tbet transcription factor axis}},
  url          = {{http://dx.doi.org/10.1093/jimmun/vkag024}},
  doi          = {{10.1093/jimmun/vkag024}},
  volume       = {{215}},
  year         = {{2026}},
}