STAT3 operates as an inflammation-dependent transcriptional switch

Keywords

• NK cells

• STAT3

• IL-15

• MCMV

Main Findings

STAT3 is a pleiotropic transcription factor activated by various cytokines. It has been shown to be immunomodulatory following IL-10 stimulation of cells but has also been associated with cellular proliferation. In this preprint, Grassman et al. evaluate the role of STAT3 in Natural killer (NK) cells in vivofollowing murine cytomegalovirus (MCMV) and in vitro upon various cytokine stimulations. Using chimeric mice models with wild type and gene knock-out NK cells, authors investigate NK cell expansion, differentiation, and gene expression. In addition, STAT3 genomic binding is assessed by CUT&TAG method.

In homeostasis and during low dose MCMV infection, STAT3 expression in NK cell is necessary for their proliferation. STAT3 is shown to compete with STAT5 (downstream of IL-15 signaling), which releases Myb expression and prevents differentiation of NK toward a more mature phenotype (CD27-CD11b+).

During high dose viral infection with MCMV in vivo, type-I IFN signalling is regulated by STAT3 in NK cells, which promote NK cell differentiation and lower proliferation. NK cells lacking STAT3 in this context proliferate much more. Following in vitro IFNa+IL-12 stimulation in the presence or not of IL-10, authors showed that STAT3 binds around Pdrm1 genomic location and is associated with higher Pdrm1 expression. Importantly, the deletion of Prdm1, which code for BLIMP1 protein promotes NK cell differentiation (lower CD27 expression).

Thus, depending on the context and cytokine environment, STAT3 affects NK cell proliferation and differentiation by competing with other STAT transcription factors in the genomic binding and consequently NK cell differentiation through the modulation of Myb and Prdm1 expression.

Limitations

• As STAT3 and STAT5 can form heterodimers, it would be important to dissect whether heterodimers are at play in the in vitro model used by the authors. The use of STAT5-/- NK cells would also be important to illustrate STAT3/STAT5 competion.

• It would be interesting to investigate what governs differential STAT3 genomic binding. Would STAT3 isoforms, differential phosphorylation, or heterodimer formation impact STAT3 genomic binding sites?

• Since there are many STAT3 inhibitors being developped, it would be interesting to study their impact in the in vivo model presented here. Similarly, how a STAT3 gain of function impact NK cell?

• Beside NK cell proliferation and differentiation, how STAT3 affect NK cell functions in the context of MCMV infection or tumor model would increase the relevance of the findings.

Significance/Novelty

With STAT3 inhibitors emerging as promising therapies for solid tumors, understanding how STAT3 regulates immune cell functions and responds to inflammation is crucial for their effective and safe use.

Credit

Reviewed by Nicolas Ruffin as part of a cross-institutional journal club between the Icahn School of Medicine at Mount Sinai, the University of Oxford, the Karolinska Institute, the MD Anderson Cancer Center, and the University of Toronto.

The author declares no conflict of interests in relation to their involvement in the review.