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International Immunology Advance Access originally published online on February 19, 2009
International Immunology 2009 21(4):379-391; doi:10.1093/intimm/dxp005
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© The Japanese Society for Immunology. 2009. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Differential control of allo-antigen-specific regulatory T cells and effector T cells by anti-CD4 and other agents in establishing transplantation tolerance

Kanji Nagahama1,2, Zoltan Fehervari1, Takatoku Oida1,3, Tomoyuki Yamaguchi1, Osamu Ogawa2 and Shimon Sakaguchi1,3

1 Department of Experimental Pathology, Institute for Frontier Medical Sciences
2 Department of Urology, Faculty of Medicine, Kyoto University, Kyoto 606-8507, Japan
3 Core Research for Evolutional Science and Technology Program, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan
4 Laboratory of Experimental Immunology, World Premier Initiative Immunology Frontier Research Center, Osaka University, Suita 565-0871, Japan

Correspondence to: S. Sakaguchi; E-mail: shimon{at}frontier.kyoto-u.ac.jp

Donor-specific graft tolerance can be established by a combination of allo-antigen exposure and manipulation of T cell function, for example by donor-specific transfusion (DST) under the cover of a non-depleting anti-CD4 mAb. Yet, the cellular basis of this graft tolerance is still obscure. This report shows that T cell-deficient BALB/c nude mice reconstituted with naive unfractionated T cells are specifically tolerized to DBA/2 skin grafts by DST and anti-CD4 mAb treatment, whereas those transferred with T cell suspensions depleted of all Foxp3+CD25+CD4+ natural regulatory T cells (Tregs) are not. The treatment inhibits Mls-1a allo-antigen-specific expansion of CD4+ non-Tregs expressing Vβ6 TCR subfamily but leaves the expansion of Vβ6-expressing Tregs unaffected, allowing the latter to selectively expand and establish donor-specific tolerance. Furthermore, anti-CD4 mAb inhibits in vitro the selective expansion of allo-antigen-specific CD4+ non-Tregs but not natural Tregs, as observed with in vitro anti-CD154 [CD40 ligand (CD40L)] mAb or rapamycin treatment. The results collectively indicate that the differential effect of biologicals and pharmacological substances on the expansion of allo-antigen-specific Tregs and effector T cells and resulting dominance of the former can be a key general mechanism underlying dominant transplantation tolerance.

Keywords: anti-CD4 antibody, CD40 ligand, donor-specific transfusion, organ transplantation, rapamycin, regulatory T cells, transplantation tolerance

Transmitting editor: K. Okumura

Received 18 September 2008, accepted 15 January 2009.


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