Integrated Chemokine and Cytokine Signaling Shapes Context-Dependent T Cell Transcriptional Programs

Although chemokine receptor engagement is classically mediated by G protein–coupled receptors, the extent to which cytokines modulate chemokine receptor signaling and transcriptional outcomes remains poorly defined. Here, we investigated how the cytokines IL-15 and IL-32α influence T-cell responses to the chemokines CXCL8 and CCL20.

Our transcriptomic analyses revealed that these cytokines and chemokines combinations generate context-dependent transcriptional programs. IL-15 and CXCL8 interactions produced dominant IL-15 like transcriptional signatures, suggesting hierarchical signaling integration. In contrast, IL-32α combined with CXCL8 elicited a distinct cooperative transcriptional profile enriched for genes related to vesicular remodeling, mTOR-associated metabolic activity, and cytoskeletal organization.