Changes in Reactivity of CD4CD25 and CD4CD25 T Cell Subsets in Transplant Tolerance.

Transplant tolerance induced in adult animals is mediated by alloantigen-specific CD4CD25 T cells, yet in many models, proliferation of CD4 T cells from hosts tolerant to specific-alloantigen is not impaired. To identify changes that may diagnose tolerance, changes in the patterns of proliferation of CD4, CD4CD25, and CD4CD25 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 CD4CD25 T cells was greater than naïve CD4 T cells. In contrast, proliferation of CD4CD25 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, CD4CD25 T cells from tolerant hosts did not proliferate to PVG, but did to Lewis, whereas naïve CD4CD25 T cells proliferate to both PVG and Lewis but not to self-DA. CD4CD25 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 CD4CD25 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 CD4CD25 T cells that mediate transplant tolerance depend on IFN-γ or IL-5 from alloactivated Th1 and Th2 cells.