Abstract
Transplant tolerance induced in adult animals is mediated by alloantigen-specific CD4+CD25+ T cells, yet in many models, proliferation of CD4+ T cells from hosts tolerant to specific-alloantigen in vitro is not impaired. To identify changes that may diagnose tolerance, changes in the patterns of proliferation of CD4+, CD4+CD25+, and CD4+CD25− T cells from DA rats tolerant to Piebald Virol Glaxo rat strain (PVG) cardiac allografts and from naïve DA rats were examined. Proliferation of CD4+ T cells from both naïve and tolerant hosts was similar to both PVG and Lewis stimulator cells. In mixed lymphocyte culture to PVG, proliferation of naïve CD4+CD25− T cells was greater than naïve CD4+ T cells. In contrast, proliferation of CD4+CD25− T cells from tolerant hosts to specific-donor PVG was not greater than CD4+ T cells, whereas their response to Lewis and self-DA was greater than CD4+ T cells. Paradoxically, CD4+CD25+ T cells from tolerant hosts did not proliferate to PVG, but did to Lewis, whereas naïve CD4+CD25+ T cells proliferate to both PVG and Lewis but not to self-DA. CD4+CD25+ T cells from tolerant, but not naïve hosts, expressed receptors for interferon (IFN)-γ and IL-5 and these cytokines promoted their proliferation to specific-alloantigen PVG but not to Lewis or self-DA. We identified several differences in the patterns of proliferation to specific-donor alloantigen between cells from tolerant and naïve hosts. Most relevant is that CD4+CD25+ T cells from tolerant hosts failed to proliferate or suppress to specific donor in the absence of either IFN-γ or IL-5. The proliferation to third-party and self of each cell population from tolerant and naïve hosts was similar and not affected by IFN-γ or IL-5. Our findings suggest CD4+CD25+ T cells that mediate transplant tolerance depend on IFN−γ or IL-5 from alloactivated Th1 and Th2 cells.
Highlights
Tolerance to transplanted tissue is alloantigen-specific, as second grafts from the same donor strain are accepted whereas thirdparty grafts are rejected [1,2,3]
Tolerance was induced by treatment of dark agouti strain of rats (DA) rats with anti-CD3 mAb (G4.18) at the time of transplantation with a heterotopic Piebald Virol Glaxo rat strain (PVG) heart graft, as described [13, 14, 19]
The proportion of lymphocyte subsets in lymph node and spleen of tolerant and naïve DA rats was similar for CD4+ T cells, CD8+ T cells, or B cells (Figure 1B)
Summary
Tolerance to transplanted tissue is alloantigen-specific, as second grafts from the same donor strain are accepted whereas thirdparty grafts are rejected [1,2,3]. Without further immunosuppression, animals accept a second graft from donor strain but reject thirdparty grafts [14] Peripheral lymphocytes from these tolerant hosts respond to specific-donor in MLC [14], contain donor-specific cytotoxic T cells [14], and react to specific-donor in graft-vs-host assays [15]. This “operational” or “split tolerance” [2] is dependent for its induction and maintenance on alloantigen-specific CD4+ T regulatory cells (Treg) [3, 10, 16, 17] especially CD4+CD25+ Treg [18,19,20]. CD4+CD25− T cells from tolerant animals are not clonally deleted and effect rejection of specific-donor grafts in adoptive hosts [10, 16, 17]
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call