CD8+ T lymphocytes regulating Th2 pathology escape neonatal tolerization

Transplantation tolerance induced by neonatal injection of semiallogeneic spleen cells is associated in several strain combinations with a pathological syndrome caused by Th2 differentiation of donor-specific CD4(+) T lymphocytes. We investigated the role of host CD8(+) T cells in the regulation of this Th2 pathology. IgE serum levels and eosinophilia significantly increased in BALB/c mice neonatally injected with (A/J x BALB/c)F(1) spleen cells when CD8(+) T cells were depleted by administration of anti-CD8 mAb or when beta(2)-microglobulin-deficient mice were used as recipients. In parallel, increased serum levels of IL-5 and IL-13 were measured in blood of tolerant CD8(+) T cell-deficient mice. Whereas neonatally injected mice were unable to generate anti-donor cytotoxic effectors, their CD8(+) T cells were as efficient as control CD8(+) T cells in reducing the severity of Th2 pathology and in restoring donor-specific cytotoxicity in vitro after in vivo transfer in beta(2)-microglobulin-deficient mice. Likewise, CD8(+) T cells from control and tolerant mice equally down-regulated the production of Th2 cytokines by donor-specific CD4(+) T cells in vitro. The regulatory activity of CD8(+) T cells depended on their secretion of IFN-gamma for the control of IL-5 production but not for IL-4 or IL-13. Finally, we found that CD8(+) T cells from 3-day-old mice were already able to down-regulate IL-4, IL-5, and IL-13 production by CD4(+) T cells. We conclude that regulatory CD8(+) T cells controlling Th2 responses are functional in early life and escape neonatal tolerization.