title: Differential control of allo-antigen-specific regulatory T cells and effector T cells by anti-CD4 and other agents in establishing transplantation tolerance.
abstract: 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-1(a) allo-antigen-specific expansion of CD4(+) non-Tregs expressing Vbeta6 TCR subfamily but leaves the expansion of Vbeta6-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.
authors.affiliation: Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Japan.
authors.forename: Kanji
authors.initials: K
authors.lastname: Nagahama
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Fehervari
authors.forename: Takatoku
authors.initials: T
authors.lastname: Oida
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Osamu
authors.initials: O
authors.lastname: Ogawa
authors.forename: Shimon
authors.initials: S
authors.lastname: Sakaguchi
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005260:Female; D007519:Isoantigens / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D020123:Sirolimus / Q000494:pharmacology; D016038:Skin Transplantation / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D023001:Transplantation Tolerance / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D007519:Isoantigens; D020123:Sirolimus