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