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...
We have previously identified donor-derived Thy1+ alphabeta T-cell receptor (TCR)+ CD4+ CD8- regulatory T-cells that suppress GVH reactivity induced by donor leukocyte infusion (DLI) after BMT. These cells develop in the recipient thymus and may play a role in the maintenance of donor-host tolerance after allogeneic BMT. In the present study, we sought to further characterize the T-cells responsible for the regulatory cell activity in our model. Lethally irradiated recipient AKR mice (H-2k) received transplants of BM from CD25-deficient (-/-) C57BL/6 mice (H-2b). Recipients of CD25-deficient BM developed more severe GVHD after DLI than did recipients of normal BM, a result that indirectly suggests that CD4+ CD25+ regulatory T-cells are important to the suppression of GVH reactivity after allogeneic BMT. GVHD was accompanied by mortality, body weight loss, and elevated percentages of T-cells from the DLI in the peripheral blood in mice that received CD25-deficient BM compared to mice that received normal BM. Both CD40-CD40L and CD28-B7 costimulatory pathways have been implicated in the generation of CD25+ regulatory T-cells. Therefore, we tested whether deficiency in either of these pathways affected the activity of donor BM-derived regulatory T-cells. The absence of CD40L did not affect the regulatory T-cells (ie, recipient mice were still protected from DLI-induced GVHD). In contrast, use of marrow from CD28-deficient mice resulted in complete loss of suppression of GVH reactivity. Thus, CD28 but not CD40L was critical for the generation and/or activation of immunoregulatory T-cells that suppressed GVHD induced by DLI. Together, the results of these experiments suggest that CD4+ CD25+ regulatory T-cells suppress GVH reactivity after BMT and that CD28 expression is indispensable for the generation of these cells.
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