Increased CD4+CD25+Foxp3+ regulatory T cells in tolerance induced by portal venous injection

He, Fan; Chen, Zhishui; Xu, Shengyuan; Cai, Ming; Wu, Min; Li, Hongzhou; Chen, Xiaoping

doi:10.1016/j.surg.2009.01.016

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Volume 145, Issue 6 , Pages 663-674, June 2009

Increased CD4⁺CD25⁺Foxp3⁺ regulatory T cells in tolerance induced by portal venous injection

Fan He, MD
- Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Zhishui Chen, MD, PhD
- Institution of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Reprint requests: Zhishui Chen, MD, PhD, Institution of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China.
Shengyuan Xu, MA
- Institution of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Ming Cai, PhD
- Institution of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Min Wu, PhD
- Institution of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Hongzhou Li, MA
- Institution of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Xiaoping Chen, MD, PhD
- Institution of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

Accepted 15 January 2009. published online 20 April 2009.

Background

A portal vein injection (PVI) of allogeneic donor antigen is known to prolong the survival of a subsequently transplanted allograft; however, the underlying mechanism remains to be clarified.

Methods

Irradiated C57BL/6 (B6) splenocytes were injected into BALB/c mice via the portal vein. Seven days after injection, the proportions of CD4⁺CD25⁺Foxp3⁺ regulatory T (Treg) cells were determined in the blood, liver, and spleen. CD4⁺ and CD8⁺ T cells were isolated from BALB/c mice that received PVI of B6 splenocytes (PVI mice), adoptively transferred into recipient BALB/c mice 1 day before B6 or third-party C3H heart transplantation, and graft survival was compared. B6 or C3H heart allografts were implanted into anti-CD25 monoclonal antibody (mAb)-treated PVI and untreated PVI mice, and graft survivals were compared. The percentages of CD4⁺CD25⁺Foxp3⁺ Treg, cytokine profiles, and ratios of apoptosis were determined in anti-CD25 mAb-treated PVI and untreated PVI mice.

Results

PVI of allogeneic cells induced antigen-specific tolerance and increased the percentage of CD4⁺CD25⁺Foxp3⁺ Treg. Adoptive transfer of CD4⁺ T cells, but not CD8⁺ T cells, from PVI mice prolonged B6 heart allograft survival. Depletion of CD4⁺CD25⁺ T cells prevented the induction of tolerance and decreased the percentage of CD4⁺CD25⁺Foxp3⁺ Treg in the CD3⁺ T-cell pool, and thus was associated with decreased production of interleukin (IL)-4 and apoptosis of T cells.

Conclusion

Increased CD4⁺CD25⁺Foxp3⁺ Treg play an important role in portal vein tolerance induction, at least partly via increasing the production of IL-4 and decreasing apoptosis of T cells.