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

ABSTRACT: Memory CD8 T cells (Tmem) are activated into innate-like killers by cytokines such as IL-12, IL-15 and IL-18; but mechanisms regulating this phenomenon (termed bystander activation) are unclear. We show that basal IL-4 signals antagonize IL-18 sensing and blunt IFNg production following bystander activation of Tmem in mice. Furthermore, IL-4 treatment can act directly on Tmem in a STAT6-dependent manner, to limit their control of a bystander bacterial infection. Nevertheless, we find that IL-4 does not simply block bystander activation but rather alters Tmem gene expression to tune effector molecule expression. Defective bystander activation of homeostatic Tmem in some strains relates, in part, to IL-4 exposure, but we show that these differences are erased in Tmem produced by TCR 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 by prior antigen experience. These findings underscore the importance of the cytokine milieu in dictating the ability of bystander CD8 Tmem to mediate pathogen control.

ORGANISM(S): Mus musculus

PROVIDER: GSE315645 | GEO | 2026/02/01

REPOSITORIES: GEO

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Project description:Some unicellular organisms exhibit collective decision-making through intercellular communication once a quorum of members sense an environmental stress. Whether T cells at different states of differentiation may also synchronize their behavior on a population basis through direct interactions remains unclear. We report that memory CD8+ T cells (TMem) directly interact with naive T cells (TN) during priming, affecting the phenotypic, functional, transcriptional and metabolic differentiation of TN-derived progeny. This previously unrecognized, contact and concentration-dependent interaction between naive (TN) and memory CD8+ T cells (TMem) directly enhanced TN effector differentiation through non-apoptotic Fas signaling resulting in downstream Akt pathway activation. TN primed with TMem exhibited significantly impaired persistence and antitumor activity compared with TN primed alone. Disruption of FasL-Fas signaling in TN cells limited differentiation and enhanced anti-tumor immunity while provision of exogenous FasL in the absence of TMem impaired anti-tumor immunity by augmenting TN differentiation. These findings reveal that the full therapeutic potential of TN-derived cells for adoptive immunotherapy requires physical separation from TMem prior to priming or antagonism of Fas-signaling. FACS-sorted in vitro differentiated TMem samples were without stimulation (0 hours) (n=3), and FACS-sorted in vitro differentiated TMem samples were stimulated using CD3-specific and CD28-specific antibodies and IL-2 for 18 (n=3) and 96 (n=3) hours. FACS-sorted naive Pmel-1 CD8+ T cell samples were without stimulation (0 hours) (n=3), and FACS-sorted TN-derived Pmel-1 CD8+ T cell samples were stimulated using CD3-specific and CD28-specific antibodies and IL-2 for 18 (n=3) and 96 (n=3) hours. FACS-sorted TN-derived Pmel-1 CD8+ T cell samples were stimulated in the presence of TMem using CD3-specific and CD28-specific antibodies and IL-2 for 18 (n=3) and 96 (n=3) hours. FACS-sorted in vitro differentiated TMem samples were stimulated in the presence of TN using CD3-specific and CD28-specific antibodies and IL-2 for 18 (n=3) and 96 (n=3) hours. All samples were done in triplicate as biological repeats.

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

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