Intragraft memory-like CD127hiCD4+Foxp3+ Tregs maintain transplant tolerance.

Area of Science:

• Immunology
• Transplantation Biology

Background:

• CD4+Foxp3+ regulatory T cells (Tregs) are vital for suppressing transplant rejection.
• The precise role and heterogeneity of Tregs within the graft microenvironment during tolerance remain unclear.

Purpose of the Study:

• To investigate the phenotypic and transcriptomic characteristics of Treg populations within lymphoid organs and islet grafts in a xenotransplant tolerance model.
• To identify specific Treg subsets responsible for maintaining transplant tolerance.

Main Methods:

• Comparison of Treg populations from lymphoid organs and grafts using phenotypic and transcriptomic analyses.
• Islet xenotransplantation in a mouse model.
• Adoptive transfer experiments in secondary hosts.
• IL-7 stimulation and STAT5 phosphorylation assessment.

Main Results:

• Tregs are essential for both the induction and maintenance of transplant tolerance.
• Heterogeneity exists within Treg populations in both lymphoid organs and grafts.
• A distinct CD127hi Treg subpopulation with memory features was identified in lymphoid organs and enriched in long-surviving grafts.
• These CD127hi Tregs exhibited a transcriptomic and phenotypic profile similar to other tissue-resident Tregs.
• Adoptive transfer of CD127hi Tregs conferred superior protection against rejection compared to naive or unselected Tregs.
• IL-7 stimulation of CD127hi Tregs activated STAT5 phosphorylation.

Conclusions:

• Memory-like CD127hi Tregs likely develop in draining lymph nodes and further differentiate within the graft.
• These Tregs share characteristics with other tissue-resident or tumor-associated Tregs.
• Engineering Tregs with these memory-like features could enhance transplant tolerance, offering potential therapeutic strategies for adoptive cell therapy.