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* Department of Surgery, University of Wisconsin, Madison, WI 53792;
Department of Microbiology, College of Medicine, Konyang University, Nonsan, South Korea;
Department of Surgery and Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210; and
Department of Pathology, University of Wisconsin and Veterans Affairs Hospital, Madison, WI 53792
Adaptive T regulatory (TR) cells mediate the suppression of donor-specific, delayed-type hypersensitivity (DTH) in tolerant organ transplant recipients. We hypothesized that cells belonging to the CD4+CD25+ T cell subset but distinct from natural TR cells may fulfill this role. To test this hypothesis, PBMC and biopsy samples from two tolerant kidney transplant recipients (K1 and K2) were analyzed. When transferred with recipient APC into a SCID mouse footpad, CD4+ T cells were hyporesponsive in DTH to donor type HLA-B Ags and derivative allopeptides. However, anti-human TGF–
1 Ab revealed a response to immunodominant allopeptides in both patients, suggesting that CD4+ T effector (TE) cells coexisted with suppressive, TGF–1-producing CD4+ TR cells. During in vitro culture, allopeptide stimulation induced both IFN-
-producing and surface TGF–1+ T cells. The relative strength of the latter response in patient K1 was inversely correlated with the level of systemic anti-donor DTH, which varied over a 6-year interval. Allopeptide-induced surface TGF–1 expression was found primarily in Forkhead box P3 (FoxP3)–negative CD4+CD25low T cells, which could adoptively transfer suppression of donor-specific DTH. Biopsy samples contained numerous surface TGF-1+ mononuclear cells that costained for CD4 and, less frequently CD25, but were negative for FoxP3. The CD4+TGF-1+ T cells were localized primarily to the tubulointerstitium, whereas TGF-1–FoxP3+CD25+ cells were found mainly in lymphoid aggregates. Thus, adaptive TR cells suppressing TE cell responses to donor allopeptides in two tolerant patients appear to be functionally and phenotypically distinct from CD4+CD25highFoxP3+ T cells.
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1 This work was supported in part by National Institutes of Health Grants R21-AI49900-01, R01-AI/HL 48624-01, and K02-AI01452, Immune Tolerance Network Grant 1814-8094 (to W.J.B.), a grant from the University of Wisconsin Medical Foundation (to J.L.), University of Wisconsin Graduate School Grant 135G144 (to Q.X.), and National Institutes of Health Grants U19-AI43900 (to S.J.K.) and R29-AI40909 and P30-CA16058 (to A.M.V.).
2 Q.X. and J.L. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. William J. Burlingham, G4/702 Clinical Science Center, 600 Highland Avenue, Madison, WI 53792. E-mail address: burlingham{at}surgery.wisc.edu
4 Abbreviations used in this paper: TR, T regulatory; DTH, delayed-type hypersensitivity; FoxP3, Forkhead box P3; LKP, leukapheresis; TE, T effector; TT, tetanus toxoid.
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