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<p>Memory CD8<sup>+</sup> T (T<sub>mem</sub>) cells are activated into innate-like killers by cytokines, including interleukin-12 (IL-12), IL-15 and IL-18; but mechanisms regulating this phenomenon (termed bystander activation) are unclear. Here we show that basal IL-4 signals antagonize IL-18 sensing and subsequent interferon-γ production during T<sub>mem</sub> cell bystander activation. IL-4 treatment can act directly on T<sub>mem</sub> cells in a STAT6-dependent manner to limit interferon-γ-mediated control of a bystander bacterial infection. IL-4 does not simply block bystander activation but tunes effector molecule expression. Strain-specific defects in bystander activation of homeostatic T<sub>mem</sub> cells partially relates to IL-4 exposure, but these differences are erased in T<sub>mem</sub> cells produced by T cell antigen receptor activation, leading to uniform IL-18 receptor expression and capacity for bystander activation/cytotoxicity. Our data demonstrate that bystander activation by inflammatory cytokines is subject to regulation by both IL-4 and prior antigen experience. These findings underscore the importance of the cytokine milieu in dictating bystander-mediated pathogen control.</p>

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IL-4–STAT6 signaling delays protective CD8+ T cell bystander activation by antagonizing IL-18 sensing

  • 期刊论文

  • 发表日期：

    2026年2月10日

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  • Nicholas J. Maurice,
  • Talia S. Dalzell,
  • Trevor N. Tankersley,
  • Ka Hyun Rhee,
  • Katharine E. Block,
  • Nicholas N. Jarjour,
  • Taylor A. DePauw,
  • Sarah M. Wall,
  • Sara E. Hamilton,
  • Stephen C. Jameson

摘要

Memory CD8+ T (Tmem) cells are activated into innate-like killers by cytokines, including interleukin-12 (IL-12), IL-15 and IL-18; but mechanisms regulating this phenomenon (termed bystander activation) are unclear. Here we show that basal IL-4 signals antagonize IL-18 sensing and subsequent interferon-γ production during Tmem cell bystander activation. IL-4 treatment can act directly on Tmem cells in a STAT6-dependent manner to limit interferon-γ-mediated control of a bystander bacterial infection. IL-4 does not simply block bystander activation but tunes effector molecule expression. Strain-specific defects in bystander activation of homeostatic Tmem cells partially relates to IL-4 exposure, but these differences are erased in Tmem cells produced by T cell antigen receptor activation, leading to uniform IL-18 receptor expression and capacity for bystander activation/cytotoxicity. Our data demonstrate that bystander activation by inflammatory cytokines is subject to regulation by both IL-4 and prior antigen experience. These findings underscore the importance of the cytokine milieu in dictating bystander-mediated pathogen control.