The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/5/1555/ $5.00
The Journal of Experimental Medicine, Volume 187, Number 10, May 18, 1998 1555-1564

Articles

CD4+ T Cell Tolerance to Parenchymal Self-Antigens Requires Presentation by Bone Marrow–derived Antigen-presenting Cells

Adam J. Adler*, David W. Marsh*, Gregory S. Yochum*, James L. Guzzo*, Ankesh Nigam{ddagger}, William G. Nelson*, and Drew M. Pardoll*

From the * Department of Oncology and the {ddagger} Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

T cell tolerance to parenchymal self-antigens is thought to be induced by encounter of the T cell with its cognate peptide–major histocompatibility complex (MHC) ligand expressed on the parenchymal cell, which lacks appropriate costimulatory function. We have used a model system in which naive T cell receptor (TCR) transgenic hemagglutinin (HA)-specific CD4+ T cells are adoptively transferred into mice expressing HA as a self-antigen on parenchymal cells. After transfer, HA-specific T cells develop a phenotype indicative of TCR engagement and are rendered functionally tolerant. However, T cell tolerance is not induced by peptide–MHC complexes expressed on parenchymal cells. Rather, tolerance induction requires that HA is presented by bone marrow (BM)–derived cells. These results indicate that tolerance induction to parenchymal self-antigens requires transfer to a BM-derived antigen-presenting cell that presents it to T cells in a tolerogenic fashion.

Key Words: peripheral tolerance • CD4+ T cells • antigen-presenting cells • adoptive T cell transfer • transgenic mice

Address correspondence to Drew Pardoll, 720 Rutland Ave., Ross 364, Baltimore, MD 21205. Phone: 410-955-7866; Fax: 410-614-0549; E-mail: dmpardol{at}welchlink.welch.jhu.edu

A.J. Adler is the recipient of an American Cancer Society Postdoctoral Fellowship and is an American Foundation For Urological Disease Research Scholar. This work was supported by a National Cancer Institute Prostate SPORE grant (CA-58236) and gifts by the Topercer family and the Telinde fund.

Gregory S. Yochum's current address is Molecular Biology Program, University of Utah, Salt Lake City, UT 84132.

Abbreviations used: BM, bone marrow; HA, hemagglutinin; NT, nontransgenic; RT, reverse transcriptase.


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