Myeloid-derived Suppressor Cells Recruit CD4(+)/Foxp3(+) Regulatory T Cells in a Murine Cardiac Allograft.
BACKGROUND
Myeloid-derived suppressor cells (MDSCs) play an important role in regulating allograft rejection in organ transplantation. On the other hand, CD3(+)/CD4(+)/FOXP3(+) regulatory T cells (Tregs) also are of vital importance in immunological tolerance. We previously revealed that adoptive transfer of MDSCs recruited Tregs in the spleen. However, it is still uncertain whether MDSCs are capable of recruiting Tregs to an allograft in vivo.


OBJECTIVE
We conducted adoptive transfer experiments of MDSCs to clarify the effects of MDSCs on Tregs in vivo.


METHODS
Gr-1(+)/CD11b(+) MDSCs were isolated from rapamycin-treated cardiac transplant (CTx) recipients (3 mg/kg, intraperitoneally on postoperative days [POD] 0, 2, 4, and 6) on POD 7 by magnetic-activated cell sorting (purity >95%). In murine heterotopic cardiac transplantation, 2 × 10(6) MDSCs were transferred into the graft aorta 5 minutes before reperfusion.


RESULTS
Flow cytometric analyses of a cardiac allograft on POD 7 showed that MDSCs derived from rapamycin-treated CTx mice (MDSCs-Rap) transfer led to significant recruitment of Tregs compared with a PBS-injected allograft. The level of programmed death ligand-1 (PD-L1) on MDSCs-Rap was higher than those from non-treated recipients. Furthermore, pathological findings also confirmed accumulation of Foxp3(+) Tregs in an allograft.


CONCLUSIONS
Induced PD-L1 on MDSCs might result in recruitment of Tregs. These results suggested that functional MDSCs possessed an ability to induce Tregs in a cardiac allograft and developed a tendency to immunological tolerance.
Department of Organ Transplantation and General Surgery, Kyoto Prefectural University of Medicine, Kajii-cho 465, Kamigyo-ku, Kyoto-prefecture, Japan. Electronic address: tsukasa@koto.kpu-m.ac.jp.
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Nakamura
Department of Organ Transplantation and General Surgery, Kyoto Prefectural University of Medicine, Kajii-cho 465, Kamigyo-ku, Kyoto-prefecture, Japan.
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T
Nakao
Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, 5 Nakauchi, Yamashina-ku, Kyoto, Japan.
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Ashihara
Department of Organ Transplantation and General Surgery, Kyoto Prefectural University of Medicine, Kajii-cho 465, Kamigyo-ku, Kyoto-prefecture, Japan.
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Yoshimura
D019264:Adoptive Transfer / Q000379:methods; D064591:Allografts / Q000276:immunology; D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D016027:Heart Transplantation; D007108:Immune Tolerance / Q000502:physiology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D000072737:Myeloid-Derived Suppressor Cells / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014184:Transplantation, Homologous
D039481:CD11b Antigen; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C509295:ITGAM protein, human; D007166:Immunosuppressive Agents; D020123:Sirolimus