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Published 5 April 2004. doi:10.1084/jem.20031012
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 7, 1017-1023
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*Kidney Transplantation
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Brief Definitive Report

 Minor H Antigen HA-1–specific Regulator and Effector CD8+ T Cells, and HA-1 Microchimerism, in Allograft Tolerance

Junchao Cai1, Junglim Lee1, Ewa Jankowska-Gan1, Richard Derks1, Jos Pool2, Tuna Mutis2, Els Goulmy2, and William J. Burlingham1

1 Department of Surgery, University of Wisconsin-Madison, Madison, WI 53792
2 Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, 2300 RC, Netherlands

Address correspondence to W.J. Burlingham, Dept. of Surgery, University of Wisconsin-Madison, Hospital and Clinics, 600 Highland Ave., Madison, WI 53792. Phone: (608) 263-0119; Fax: (608) 263-7652; email: burlingham{at}surgery.wisc.edu

The role of the hematopoietic lineage-restricted minor histocompatibility (H) antigen HA-1 in renal allograft tolerance was explored. We obtained peripheral blood samples from three recipients of histocompatibility leukocyte antigen (HLA)–matched, HA-1–mismatched renal transplants, one of which had discontinued immunosuppression >30 yr ago while sustaining normal kidney function. Peripheral blood mononuclear cells (PBMCs) were injected into the footpads of severe combined immunodeficiency mice to measure human delayed type hypersensitivity (DTH) responses. All three patients manifested regulated DTH responses to HA-1H peptide. By differential tetramer staining intensities, we observed two distinct minor H antigen HA-1–specific CD8+ T cell subsets. The one that stained dimly had the characteristics of a T regulatory (TR) cell and produced interleukin (IL) 10 and/or transforming growth factor (TGF) ß. These HA-1–specific TR cells coexisted with bright tetramer-binding CD8+ T effector (TE) cells. The CD8+ TE cells mediated HA-1–specific DTH and produced interferon-{gamma}. Suppression of these TE functions by TR cells was TGFß, IL-10, and cytotoxic T lymphocyte–associated antigen 4 dependent. In addition, HA-1 microchimerism was detected in two recipients, primarily in the dendritic cell fraction of the PBMCs. This is the first demonstration of coexisting CD8+ memory TR and TE cells, both specific for the same HA-1 antigen, in the context of renal allograft tolerance.

Key Words: regulatory T cells • immunoregulation • peripheral tolerance • kidney transplantation

J. Cai and J. Lee contributed equally to this work.

The online version of this article contains supplemental material.

The present address of J. Cai is Terasaki Foundation, Los Angeles, CA 90064.

The present address of J. Lee is Yonsei University Medical School, Seoul 110-744 Korea.

The present address of T. Mutis is University Medical Center, Utrecht, 3584 CX, Netherlands.


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