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First Comprehensive Analysis of Full-Length and Δ2 Foxp3 Isoforms Distribution in PBMCs from Healthy Volunteers
Manuel Fernández-Delgado1, Luis Sendra2,3, María José Herrero2,3
1Service of Hematology and Hemotherapy, Hospital General Universitario de Castellón, 12004 Castelló de la Plana, Spain.
Biomolecules
|July 28, 2026
Summary
Regulatory T cell (Treg) master regulator FOXP3 has two isoforms, FOXP3-FL and FOXP3-Δ2, with distinct distributions in immune cells. FOXP3-FL dominates in Tregs, while FOXP3-Δ2 is found in other leukocytes, influencing immune checkpoint expression.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- FOXP3 is the key regulator of regulatory T cells (Tregs).
- Two main FOXP3 isoforms, FOXP3-FL and FOXP3-Δ2, exist, but their distribution and role in non-Treg cells are unclear.
- Immune checkpoint proteins like PD-1 and CTLA-4 are crucial for immune regulation.
Purpose of the Study:
- To investigate the distribution of FOXP3-FL and FOXP3-Δ2 isoforms across various peripheral blood leukocyte populations.
- To examine the relationship between FOXP3 isoform expression and immune checkpoint expression (PD-1, CTLA-4).
- To establish a baseline understanding of FOXP3 isoform and checkpoint expression in healthy individuals.
Main Methods:
- Utilized multiparametric flow cytometry for isoform-specific detection of FOXP3-FL and FOXP3-Δ2.
- Analyzed peripheral blood samples from healthy donors.
- Quantified FOXP3 isoforms and immune checkpoints (PD-1, CTLA-4) in CD4+ T cells (CD4+CD25+, CD4+CD25-), CD8+ T cells, monocytes, and neutrophils.
Main Results:
- FOXP3-FL was predominant in CD4+CD25+ T cells (Tregs).
- FOXP3-Δ2 was more frequent in CD8+ T cells, monocytes, and neutrophils, though at low overall frequencies.
- In CD4+ T cells, PD-1 expression was higher than CTLA-4, with FOXP3-Δ2+ cells showing higher PD-1 levels than FOXP3-FL+ cells.
- Immune checkpoint expression was limited in non-CD4+ populations.
Conclusions:
- FOXP3-FL appears to play a primary role in immune tolerance in healthy individuals.
- The distinct distribution of FOXP3 isoforms suggests specialized functions across different immune cell types.
- Findings provide a reference for future studies on immune-mediated diseases.
