CD8 ⁺ regulatory T cells generated by neonatal recognition of peripheral self-antigen

Abstract

In comparison with CD4 ؉ regulatory T cells, the generation and function of immunomodulatory CD8 ؉ T cells is less well defined. Here we describe the existence of regulatory anti-K b -specific CD8 ؉ T cells that are rendered tolerant during neonatal life via antigen contact exclusively on keratinocytes. These regulatory T cells maintain tolerance during adulthood as they prevent K b -specific graft rejection by naïve CD8 ؉ T cells. Third-party immune responses remain unaffected. Up-regulation of TGF-␤1 and granzyme B in the regulatory CD8 ؉ T cell population suggests the involvement of these molecules in common suppressive pathways shared with CD4 ؉ regulatory T cells. In summary, CD8 ؉ regulatory T cells can be induced extrathymically through antigen contact on neonatally accessible parenchymal cells and maintain tolerance throughout adult life.immune regulation ͉ parenchymal cells ͉ tolerance

Dickkopf-3, an immune modulator in peripheral CD8 T-cell tolerance

“…CD8 T-cell tolerance in Des.KK b mice is based, at least in part, on the capacity of neonatally induced tolerant Des CD8 T cells to regulate naive Des CD8 T cells that left the thymus at a time when the K b antigen in the skin was no longer accessible (15). To clarify whether DKK3 is crucial for the maintenance of CD8 T-cell tolerance during adulthood, we blocked its function by administering neutralizing DKK3-specific antibodies to adult tolerant Des.KK b mice and then assessed CD8 T-cell reactivity against autologous skin grafts.…”

“…In Des.KK b mice, tolerance to the self-antigen K b is mediated by a CD8 T-cell population with regulatory capacity (15). In identifying molecular mediators of this dominant form of peripheral T-cell tolerance, quantitative RT-PCR analysis of ex vivo isolated tolerant, naive, and activated Des CD8 T cells was performed for gene products involved in tolerance induction (15). Naive Des CD8 T cells were isolated from untreated Des.Rag2 −/− mice.…”

“…Experimental procedures were approved by the Regierungspräsidium (Karlsruhe, Germany). Thymectomy and skin transplantation have been previously described in detail (13,15). In addition, these mice received 1 mg of either anti-Dkk3 or isotype control antibody i.p.…”

“…One day after transfer, recipient mice received P815.K b .B7 tumor cells. Control Dkk3 −/− .Des.KK b mice were treated in the same way and received purified CD8 T cells that were specific for the SV40 large T antigen [TCR 8, which does not cross-react with the K b antigen (15,23)]. P815.K b .B7 tumors were rejected in these control mice due to activation of DKK3-deficient T cells that remain after depletion and/or new thymic emigrants (Fig.…”

“…Deletion of neonatal CD8 T cells in 12-d-old Des.KK b mice abrogated tolerance, as they rejected a K b -positive graft, whereas thymectomy at 2 wk of age did not reverse the tolerant state (13). Tolerant Des CD8 T cells were shown to have regulatory capacity, as they down-modulated the reactivity of adoptively transferred naive T cells to the cognate K b antigen (15).…”