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

Abstract

In healthy individuals, T cells react against incoming pathogens, but remain tolerant to self-antigens, thereby preventing autoimmune reactions. CD4 regulatory T cells are major contributors in induction and maintenance of peripheral tolerance, but a regulatory role has been also reported for several subsets of CD8 T cells. To determine the molecular basis of peripheral CD8 T-cell tolerance, we exploited a double transgenic mouse model in which CD8 T cells are neonatally tolerized following interaction with a parenchymal self-antigen. These tolerant CD8 T cells have regulatory capacity and can suppress T cells in an antigen-specific manner during adulthood. Dickkopf-3 (DKK3) was found to be expressed in the tolerant CD8 T cells and to be essential for the observed CD8 T-cell tolerance. In vitro, genetic deletion of DKK3 or blocking with antibodies restored CD8 T-cell proliferation and IL-2 production in response to the tolerizing self-antigen. Moreover, exogenous DKK3 reduced CD8 T-cell reactivity. In vivo, abrogation of DKK3 function reversed tolerance, leading to eradication of tumors expressing the target antigen and to rejection of autologous skin grafts. Thus, our findings define DKK3 as a immune modulator with a crucial role for CD8 T-cell tolerance.immune tolerance | parenchymal cells | autoimmunity

Tubular Dickkopf-3 promotes the development of renal atrophy and fibrosis

“…We have recently demonstrated that DKK3 can act as a tissue-derived immune modulator that influences type and strength of local T cell responses in models of peripheral tolerance, transplantation, and autoimmune disease (27)(28)(29). We have found that DKK3 is expressed during kidney development, which occurs by a mesenchymal-epithelial transition.…”

“…In order to assess whether direct blockade of DKK3 protein could corroborate the beneficial effect of the genetic DKK3 abrogation and to investigate the therapeutic potential of antibody-mediated DKK3 blockade, we treated WT UUO mice with either an anti-DKK3 monoclonal antibody or an isotype control. The specificity of the DKK3 antibody has been shown in experiments in which anti-DKK3 selectively targeted regulatory CD8 + T cells positive for DKK3 (28). The first antibody injection was done at surgery, followed by applications on every third day ( Figure 2A).…”

“…UUO-induced C57BL/6 mice were divided into two groups and received either the anti-DKK3 4.22 monoclonal antibody (28) or the MOPC21 antibody (Bio X Cell; 4666-3/0313 BE0083) as isotype control. In both cases, the first injection was made immediately after surgery with 1.0 mg of the assigned antibody.…”

Downregulation of Dickkopf-3 disrupts prostate acinar morphogenesis through TGF-β/Smad signaling

“…A variety of mechanisms have been proposed to account for the inhibitory effects of Dkk-3 on tumor cell proliferation in cancer of the prostate and other organs (Abarzua et al, 2005;Kashiwakura et al, 2008;Lee et al, 2009;Lodygin et al, 2005;Yue et al, 2008). Despite the tumor suppressor activities of Dkk-3, homozygous deletion of the Dkk3 gene in mice has only minor effects on blood cell counts, lung ventilation and behaviour, with no reported increase in mortality or spontaneous tumor formation (del Barco Barrantes et al, 2006;Papatriantafyllou et al, 2012). A clue to the possible role of Dkk-3 in normal tissues comes from siRNA studies in prostate epithelial cells, where Dkk-3 expression is required for formation of acini in three-dimensional (3D) Matrigel cultures (Kawano et al, 2006).…”

Dickkopf-3 Acts as a Modulator of B Cell Fate and Function

“…It is also present in the blood (27). We have shown previously that DKK3 could limit CD8 T cell reactivity (28). Therefore, we were interested in whether DKK3 could also affect B cell function.…”