Human CD39^hi regulatory T cells present stronger stability and function under inflammatory conditions

Area of Science:

• Immunology
• Cell Biology
• Autoimmune Diseases

Background:

• Autoimmune diseases involve an imbalance between regulatory T cells (Tregs) and effector T cells.
• Pro-inflammatory cytokines can destabilize natural CD4+Foxp3+ Tregs.

Purpose of the Study:

• To investigate the functional stability of human CD39-high (CD39^hi) and CD39-low (CD39^low) Tregs under inflammatory conditions.
• To explore the therapeutic potential of CD39^hi Tregs in autoimmune disease models.

Main Methods:

• Human Tregs were expanded in vitro and sorted into CD39^hi and CD39^low subsets.
• The stability and function of these subsets were assessed under pro-inflammatory conditions (IL-1β and IL-6) in vitro and in vivo.
• Protection against xenograft versus host disease was evaluated in a mouse model.

Main Results:

• CD4⁺CD39^hi Tregs maintained stable Foxp3 expression, while CD4⁺CD39^low Tregs lost Foxp3 and differentiated into effector T cells.
• CD39^hi Tregs exhibited reduced expression of IL-1βR and IL-6R, leading to decreased STAT1 and STAT3 activation.
• CD4⁺CD39^hi Tregs, but not CD4⁺CD39^low Tregs, conferred protection in a xenograft versus host disease mouse model.

Conclusions:

• CD39 expression is critical for Treg stability in inflammatory environments.
• CD39^hi Tregs represent a stable and functional subset with therapeutic potential for autoimmune diseases.
• Targeting CD39^hi Tregs may offer a novel treatment strategy for autoimmune conditions.