Defects in CD8⁺ T cell suppression by Foxp3-ΔE2 expressing regulatory T cells

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• Regulatory T cells (Tregs) are crucial for preventing autoimmunity.
• FOXP3 is a key transcription factor programming Treg suppressive functions.
• Two FOXP3 isoforms, FOXP3-FL and FOXP3-ΔE2, exist, with FOXP3-ΔE2 linked to autoimmune diseases.

Purpose of the Study:

• To investigate the impact of the FOXP3-ΔE2 isoform on Treg function and immune responses.
• To understand the mechanisms underlying Treg dysfunction in the presence of FOXP3-ΔE2.

Main Methods:

• Utilized Foxp3-ΔE2 mice for experimental studies.
• Employed influenza virus infection models.
• Conducted transcriptomic and chromatin accessibility analyses on Tregs.
• Assessed T cell responses, cytokine responsiveness, and immune cell localization.

Main Results:

• Foxp3-ΔE2 mice exhibited enhanced CD8+ T cell responses during influenza infection.
• Tregs expressing FOXP3-ΔE2 showed impaired programming, reduced expression of inhibitory molecules (e.g., IL2RA), and diminished IL-2 responsiveness.
• FOXP3-ΔE2 Tregs displayed altered chemokine receptor expression, leading to reduced localization to inflamed lymph node T cell zones.
• Reciprocally, CD8+ T cells from Foxp3-ΔE2 mice showed increased IL-2 responsiveness.

Conclusions:

• Treg programming by the FOXP3-ΔE2 isoform compromises suppressive capacity.
• FOXP3-ΔE2-mediated Treg dysfunction leads to unrestrained CD8+ T cell activity and aberrant immune responses.
• These findings highlight the critical role of FOXP3 splicing in maintaining immune homeostasis.