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Alloreactive T Cell Responses and Acute Rejection of Single Class II MHC-Disparate Heart Allografts Are under Strict Regulation by CD4⁺CD25⁺ T Cells¹

Soren Schenk^*, Danielle D. Kish, Chunshui He, Tarek El-Sawy^,, Eise Chiffoleau^¶, Chuangqui Chen^¶, Zihao Wu^¶, Sigrid Sandner^||, Anton V. Gorbachev, Kiyotaka Fukamachi^*, Peter S. Heeger^,,, Mohamed H. Sayegh^||, Laurence A. Turka^2,¶ and Robert L. Fairchild^2,3,,,

Departments of ^* Biomedical Engineering and Immunology, and The Glickman Urological Institute, Cleveland Clinic Foundation, Cleveland, OH 44195; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106; ^¶ Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104; and ^|| Transplant Research Center, Brigham & Women’s Hospital and Children’s Hospital Boston, Harvard Medical School, Boston, MA 02115

Skin but not vascularized cardiac allografts from B6.H-2^bm12 mice are acutely rejected by C57BL/6 recipients in response to the single class II MHC disparity. The underlying mechanisms preventing acute rejection of B6.H-2^bm12 heart allografts by C57BL/6 recipients were investigated. B6.H-2^bm12 heart allografts induced low levels of alloreactive effector T cell priming in C57BL/6 recipients, and this priming was accompanied by low-level cellular infiltration into the allograft that quickly resolved. Recipients with long-term-surviving heart allografts were unable to reject B6.H-2^bm12 skin allografts, suggesting potential down-regulatory mechanisms induced by the cardiac allografts. Depletion of CD25⁺ cells from C57BL/6 recipients resulted in 15-fold increases in alloreactive T cell priming and in acute rejection of B6.H-2^bm12 heart grafts. Similarly, reconstitution of B6.Rag^–/– recipients with wild-type C57BL/6 splenocytes resulted in acute rejection of B6.H-2^bm12 heart grafts only if CD25⁺ cells were depleted. These results indicate that acute rejection of single class II MHC-disparate B6.H-2^bm12 heart allografts by C57BL/6 recipients is inhibited by the emergence of CD25⁺ regulatory cells that restrict the clonal expansion of alloreactive T cells.

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