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Published online 9 May 2005 doi:10.1084/jem.20042307
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 10, 1615-1625
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ARTICLE

 The macrophage F4/80 receptor is required for the induction of antigen-specific efferent regulatory T cells in peripheral tolerance

Hsi-Hsien Lin1,4, Douglas E. Faunce2,3, Martin Stacey1, Ania Terajewicz2, Takahiko Nakamura2, Jie Zhang-Hoover2,7, Marilyn Kerley5, Michael L. Mucenski6, Siamon Gordon1, and Joan Stein-Streilein2,7

1 Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, England UK
2 Schepens Eye Research Institute, Harvard Medical School, Boston, MA 02114
3 National Eye Institute Training Program in the Molecular Bases of Eye Diseases, Bethesda, MD 20892
4 Department of Microbiology and Immunology, Chang Gung University, Tao-Yuan 333, Taiwan
5 Life Sciences Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831
6 Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229
7 Pulmonary and Critical Care Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115

CORRESPONDENCE Joan Stein-Streilein: jstein{at}vision.eri.harvard.edu OR Siamon Gordon: christine.holt{at}path.ox.ac.uk

We show that the mouse macrophage-restricted F4/80 protein is not required for the development and distribution of tissue macrophages but is involved in the generation of antigen-specific efferent regulatory T (T reg) cells that suppress antigen-specific immunity. In the in vivo anterior chamber (a.c.)–associated immune deviation (ACAID) model of peripheral tolerance, a.c. inoculation of antigen into F4/80–/– mice was unable to induce efferent T reg cells and suppress delayed-type hypersensitivity (DTH) responses. Moreover, the use of anti-F4/80 mAb and F4/80–/– APCs in an in vitro ACAID model showed that all APC cells in the culture must be able to express F4/80 protein if efferent T reg cells were to be generated. In a low-dose oral tolerance model, WT but not F4/80–/– mice generated an efferent CD8+ T reg cell population that suppressed an antigen-specific DTH response. Peripheral tolerance was restored in F4/80–/– mice by adoptive transfer of F4/80+ APCs in both peripheral tolerance models, indicating a central role for the F4/80 molecule in the generation of efferent CD8+ T reg cells.

Abbreviations used: Ab, antibody; a.c., anterior chamber; ACAID, anterior chamber–associated immune deviation; BMAPCs, bone marrow–derived APCs; DTH, delayed-type hypersensitivity; EGF, epidermal growth factor; EMR, EGF module–containing mucin-like hormone receptor; ES, embryonic stem; LAT, local adoptive transfer; PE, phycoerythrin; PEC, peritoneal exudate cells; TM7, seven-span transmembrane; T reg, regulatory T.

H.-H. Lin and D.E. Faunce contributed equally to this work.


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