Dynamic integration of CXCL8 or CCL20 signaling with IL-15 or IL-32α reprograms human T-cell functional plasticity.

Chemokines CXCL8 and CCL20 can influence T cell responses to cytokines, affecting migration and activation in a context-dependent manner.

Summary and findings

This study investigated the effects of CXCL8 and CCL20 on human T cell responses to IL-15 and IL-32α. Peripheral blood T cells from healthy donors were evaluated for receptor expression and functional activity. The findings indicate that chemokines can influence T cell migration and transcriptional responses.

Abstract

<h4>Introduction</h4>Tissue-derived chemokines can direct immune cell migration by engaging specific receptors, thereby controlling the localization and trafficking of immune cells within tissues. However, how chemokines modulate cytokines-driven transcriptional programs in T cells remain unclear. This study investigated how CXCL8 and CCL20 influence human T cell responses to IL-15 and IL-32α.<h4>Methods</h4>Peripheral blood T cells from health donors were evaluated for the expression and functional activity of the chemokine receptors CCR6, CXCR1, and CXCR2. Chemokine induced migration was assessed using <i>in vitro</i> migration assays. T cells were stimulated with CCL20 or CXCL8 alone or in combination with IL-15 or IL-32α, and transcriptional responses were characterized by transcriptomic profiling. Selected transcriptional findings were further evaluated through functional and protein-level assays.<h4>Results</h4>Peripheral blood T cells expressed CCR6, CXCR1, and CXCR2, which were downregulated during <i>vitro</i> culture, but remained functionally responsive in migration assays, highlighting the influence of the microenvironmental on receptor expression. Transcriptomic profiling showed that CCL20 and CXCL8 independently reprogrammed GPCR-associated networks involved in migration, cytoskeletal dynamics, adhesion, and chemokine scavenging. IL-15 induced robust JAK/STAT-dependent inflammatory and survival programs together with CISH upregulation, indicating coordinated activation and negative-feedback regulation. In contrast, IL-32α modulated PI3K/AKT, adhesion, and NOTCH1-related pathways and was associated with increased T cell proliferation. Combined stimulation revealed context-dependent integration of these signaling programs. IL-15 plus CCL20 enhanced inflammatory and migratory signatures, whereas CXCL8 plus IL-15 produced a transcriptional profile largely dominated by IL-15. IL-32α plus CXCL8 induced cooperative programs involving vesicular remodeling, mTOR-associated metabolism, cytoskeletal organization, and cell-cycle regulation.<h4>Discussion</h4>These findings demonstrated that chemokine and cytokine signals are integrated in a context-dependent manner to regulate T cells migration, activation, survival and proliferation. Rather than acting solely as chemoattractant, CCL20 and CXCL8 can reshape cytokine-driven transcriptional profile programs, revealing additional regulatory layer that may contribute to T cell functional plasticity within inflammatory and tumor microenvironment.

Limitations

Not reported in abstract.

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