Regulatory T cell therapy promotes TGF-β and IL-6-dependent pro-inflammatory Th17 cell generation by reducing IL-2

Area of Science:

• Immunology
• Cell Biology

Background:

• CD4+Foxp3+ regulatory T cells (Tregs) are crucial for immune tolerance and preventing inflammation.
• Tregs are investigated for treating autoimmune diseases and graft-versus-host disease (GvHD).
• Clinical application of Treg therapy faces significant challenges.

Purpose of the Study:

• To investigate the impact of adoptive Treg therapy on pathogenic T helper 17 (Th17) cell differentiation.
• To elucidate the mechanisms by which Tregs influence Th17 cell polarization.
• To identify strategies for improving the efficacy of Treg-based therapies.

Main Methods:

• Murine models of inflammatory bowel disease (IBD) and experimental autoimmune encephalomyelitis (EAE).
• Analysis of T cell differentiation, cytokine secretion (IL-2, IL-6, TGF-β), and signaling pathways (STAT3, STAT5).
• Pharmacological blockade of the IL-6/STAT3 signaling pathway.

Main Results:

• Adoptive Treg therapy promoted IL-6 and TGF-β-dependent pathogenic Th17 cell differentiation in IBD and EAE models.
• Tregs increased the p-STAT3/p-STAT5 ratio in effector T cells by suppressing and consuming IL-2, promoting Th17 differentiation.
• IL-2 signaling deficiency enhanced Th17 cell pro-inflammatory properties.
• Blocking IL-6/STAT3 signaling reversed pathogenic Th17 differentiation and improved Treg therapy efficacy.

Conclusions:

• Treg therapy can inadvertently promote pathogenic Th17 cells via IL-2 and IL-6/STAT3 signaling.
• Targeting the IL-6/STAT3 pathway can overcome this limitation and enhance Treg therapy outcomes.
• Findings offer a potential strategy to advance clinical Treg therapy for immune-mediated diseases.