CD8+ T Lymphocytes Regulating Th2 Pathology Escape Neonatal Tolerization

Abstract

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 × BALB/c)F1 spleen cells when CD8+ T cells were depleted by administration of anti-CD8 mAb or when β2-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 β2-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-γ 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.

CD8 T Cells Modulate CD4 T-Cell and Eosinophil-Mediated Pulmonary Pathology in Pneumocystis Pneumonia in B-Cell-Deficient Mice

“…29 Additionally, accumulation of eosinophils in the lung is exacerbated by CD8 depletion in mouse models of RSV infection 30 and allergic asthma. 31 Observations such as these have lead to a resurgence in the study of putative CD8-positive regulatory or suppressor cells.…”

Regulation of Th2 Responses and Allergic Inflammation through Bystander Activation of CD8+ T Lymphocytes in Early Life

“…Considering the neonates, we and other investigators reported that regulatory CD8 + T cells controlling Th2 pathology are effective (20,21). In both cases, the induction of IFN-g-producing CD8…”

Th17 Alloimmunity Prevents Neonatal Establishment of Lymphoid Chimerism in IL-4-Deprived Mice

“…Neutralization of IL-4 significantly decreased the percentages of all these donor cell types without completely eliminating them. We next investigated the effects of early neutralization of IL-4 on the Th2-type pathology induced by neonatal alloimmunization (19). As expected, F 1 -treated mice developed splenomegaly and produced high levels of serum IgE when compared to untreated mice ( Figure 1D).…”

“…The injection of (A/J x BALB/c) F 1 spleen cells into BALB/c neonates induces lymphoid chimerism, immune polarization and transplantation tolerance of donor-type skin allografts (9,(18)(19)(20). We first evaluated the effects of perinatal administration of anti-IL-4 mAb on neonatal transplantation acceptance and Th2-type responses.…”