Defining Human Regulatory T Cells beyond FOXP3: The Need to Combine Phenotype with Function

Area of Science:

• Immunology
• Cell Biology

Background:

• Regulatory T cells (Tregs) are vital for maintaining immune homeostasis and self-tolerance.
• Reduced Treg function or numbers are linked to autoimmune diseases.
• Current definitions often rely on markers like FOXP3, but this is insufficient due to transient expression and FOXP3-negative Tregs.

Purpose of the Study:

• To review the heterogeneity of human Tregs in terms of phenotype and function.
• To highlight the limitations of using phenotype alone for Treg identification.
• To emphasize the need for functional assays in defining and categorizing Tregs.

Main Methods:

• Review of existing literature on Treg markers and function.
• Analysis of multiparametric data on Treg phenotypes.
• Discussion of candidate regulatory molecules and their limitations.

Main Results:

• No single marker or combination reliably defines all Tregs.
• FOXP3 expression is not exclusive to Tregs and can be transiently induced.
• Some Tregs, like Tr1 cells, do not express FOXP3.
• Functional capacity to inhibit immune responses is the definitive Treg characteristic.

Conclusions:

• Human Tregs are highly heterogeneous in both phenotype and function.
• Phenotypic markers alone are inadequate for unambiguous Treg identification.
• Characterizing Tregs requires a combination of phenotypic analysis and functional assessment of suppressive capacity.