CD200 is a novel p53-target gene involved in apoptosis-associated immune tolerance

Abstract

During apoptotic cell death, biochemical processes modify self-proteins and create potential autoantigens. To maintain self-tolerance in the face of natural cell turnover, the immune system must prevent or control responses to apoptosisassociated autoantigens or risk autoimmunity. The molecular mechanisms governing this process remain largely unknown. Here, we show that expression of the immunoregulatory protein CD200 increases as murine dendritic cells (DCs) undergo apoptosis. We define CD200 as a p53-target gene and identify both p53-and caspase-dependent pathways that control CD200 expression during apoptosis. CD200 expression on apoptotic DCs diminishes proinflammatory cytokine production in response to self-antigens in vitro and is required for UVB-mediated tolerance to haptenated self-proteins in vivo. Up-regulation of CD200 may represent a novel mechanism, whereby immune reactivity to apoptosis-associated self-antigens is suppressed under steady state conditions. IntroductionAs a result of natural cell turnover, cells in peripheral tissues continually undergo apoptosis. These apoptotic cells are associated with a distinct lack of inflammation, leading to the initial perception that the process of apoptosis is immunologically silent and passive. 1 However, it is now clear that apoptotic cells do not just quietly disappear. Instead, they actively inhibit immune responses by providing immunoregulatory signals directly to cells of the immune system. For example, when added to human lymphocyte cultures stimulated with lipopolysaccharide, apoptotic cells inhibit production of proinflammatory cytokines such as tumor necrosis factor ␣ (TNF-␣), interleukin 1 (IL-1), and IL-12 and promote the production of the anti-inflammatory cytokine IL-10. 2 T-cell activation is inhibited when apoptotic cells are added to splenocytes in the presence of Con A. 3 Macrophages that have ingested apoptotic cells increase production of anti-inflammatory cytokines and inhibit production of proinflammatory cytokines. 4 Furthermore, immature dendritic cells (DCs) that have taken up apoptotic cells have a compromised ability to mature into immunostimulatory antigen-presenting cells (APCs). 5 Given their immunosuppressive capacity, it has been suggested that apoptotic cells generated during natural cell turnover play a central role in the establishment and maintenance of peripheral self-tolerance. 6 Immature DCs and monocytes traffic through tissues, phagocytose apoptotic cells, and migrate to lymphoid tissue 7 ; DCs that have ingested apoptotic cells process and present apoptotic cell-derived peptides on major histocompatibility complex (MHC) class I and class II molecules 8 ; and DCs that have taken up apoptotic cells fail to initiate productive T-cell responses, possibly through the induction of regulatory T cells. 9,10 Patients with autoimmune diseases have abnormal immune responses to self-peptides generated during apoptosis, suggesting that mechanisms exist in healthy individuals that suppress immunoreactivity to apoptosis-associat...

Long Term Potentiation Is Impaired in Membrane Glycoprotein CD200-deficient Mice

“…Diverse immunomodulatory roles for CD200 have been reported; these include antigen-specific T cell responses, suppression of regulatory T cells (2), cytotoxic T cell-mediated tumor suppression (3), graft survival (4), and apoptosis-associated immune tolerance (5).…”

Analysis of the Impact of CD200 on Neurodegenerative Diseases

“…Significantly, and consistent with the findings obtained in vitro, this is dependent on CD200, since tolerance was absent when this experiment was conducted in CD200-deficient mice. The data suggest that CD200-CD200R interaction may be a key event in ensuring that inflammatory changes do not accompany steady-state ongoing apoptosis (Rosenblum et al, 2004). Interestingly several studies have highlighted a role for CD200 in tolerance following transplants (Clark et al, 2008, Gorczynski et al, 2009 …”

“…Recent data have indicated that up to 75% of apoptotic CD11c + cells express CD200, whereas about one third of non-apoptotic CD11c + cells express CD200; the evidence indicates that expression of CD200 is p53-and caspase-dependent. Similarly γ-irradiation, which induces apoptosis in C1498 leukemia cells, is associated with increased expression of CD200 (Rosenblum et al, 2004). It has been proposed that CD200 also plays a role in tolerance.…”

CD200:CD200R-Mediated Regulation of Immunity

“…Following induction of apoptosis in murine DCs, CD200 expression was markedly increased by both p53-and caspase-dependent pathways. The increased expression on apoptotic DCs in turn decreased proinflammatory cytokine production in response to self-antigens in vitro and was required for UVB-mediated tolerance to haptenated self-proteins in vivo [44].…”