Induction of surface CCR4 and its functionality in mouse Th2 cells is regulated differently during Th2 development

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• T helper cell type 1 (Th1) and Th2 cells express distinct chemokine receptors.
• The induction mechanisms of Th2 chemokine receptors, such as CC chemokine receptor 4 (CCR4), remain largely unknown compared to Th1 receptors.

Purpose of the Study:

• To investigate the induction of CCR4 surface expression and ligand responsiveness during Th2 cell differentiation.
• To compare CCR4 induction with that of a Th1 chemokine receptor, CXC chemokine receptor 3 (CXCR3).

Main Methods:

• Stimulation of resting T cells with anti-CD3/anti-CD28 in the presence of specific cytokines and antibodies.
• Reculturing cells without T cell receptor (TCR) stimulation.
• Assessing chemokine binding and chemotaxis assays.
• Evaluating CCR4 expression and functionality in IL-4-deficient and STAT6-deficient T cells.

Main Results:

• CCR4 expression was induced early after stimulation, but functionality (chemokine binding, chemotaxis) emerged later during Th2 differentiation.
• CXCR3 expression and functionality were induced after TCR stimulation and reculturing.
• CCR4 induction and responsiveness were dependent on interleukin-4 (IL-4) and signal transducer and activator of transcription 6 (STAT6) signaling.
• Recombinant IL-4 restored CCR4 expression and function in IL-4-deficient cells but not in STAT6-deficient cells.

Conclusions:

• CCR4 expression and functionality induction are regulated by the IL-4/STAT6 signaling pathway.
• CCR4 functionality is not directly correlated with its surface expression levels.
• CCR4 function acquisition occurs at later stages of Th2 cell differentiation, distinct from initial surface expression.