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Autoimmunity in MFG-E8–deficient mice is associated with altered trafficking and enhanced cross-presentation of apoptotic cell antigens
YuFeng Peng, Keith B. Elkon
YuFeng Peng, Keith B. Elkon
Published May 2, 2011
Citation Information: J Clin Invest. 2011;121(6):2221-2241. https://doi.org/10.1172/JCI43254.
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Research Article Autoimmunity Article has an altmetric score of 6

Autoimmunity in MFG-E8–deficient mice is associated with altered trafficking and enhanced cross-presentation of apoptotic cell antigens

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Abstract

Apoptotic cells must be rapidly cleared, as defects in this process can lead to autoimmunity. Milk fat globule EGF factor 8 (MFG-E8) binds to apoptotic cells and facilitates their removal through interaction with phagocytes. Mice deficient in MFG-E8 develop lupus-like autoimmunity associated with accumulation of apoptotic cells in vivo. Here, we have shown that MFG-E8 controls phagocytic ingestion of cell fragments as well as their intracellular processing into MHC-antigen complexes. Older Mfge8–/– mice spontaneously developed dermatitis associated with CD8+ T cell infiltration and striking activation of effector memory CD8+ T cells. CD8+ T cell responses to both exogenous and endogenous apoptotic cell–associated antigens were enhanced in Mfge8–/– mice. MFG-E8 deficiency accelerated the onset of disease in a mouse model of autoimmune diabetes. Enhanced CD8+ T cell responses were attributed to increased cross-presentation by DCs along with increased detection of antigen-MHCI complexes. Intracellular trafficking analysis revealed that intact apoptotic cells ingested by wild-type DCs rapidly fused with lysosomes, whereas smaller fragments persisted in Mfge8–/– DC endosomal compartments for 24 hours. These observations suggest that MFG-E8 deficiency promotes immune responses to self antigens not only by delaying the clearance of dying cells but also by altering intracellular processing, leading to enhanced self-antigen presentation.

Authors

YuFeng Peng, Keith B. Elkon

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Figure 14

MFG-E8 deficiency enhances the generation of the OVAp/ MHCI complex.

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MFG-E8 deficiency enhances the generation of the OVAp/ MHCI complex.
(A)...
(A) Day-6 immature BMDCs were incubated with Apo-OVA for 4, 6, and 24 hours. The generation of OVAp/MHCI complexes was evaluated by intracellular staining with the 25D1.16 antibody and the percentages of 25D1.16+CD11c+ cells shown. Right: percentages of CD11c+25D1.16+ cells at 24 hours from 4 independent experiments. ***P = 0.006. Histogram below compares the intensities of 25D1.16 staining (histogram: blue, WT; red, Mfge8–/– BMDCs). MFIs are shown on the top (Mfge8–/– versus WT). Right: results from 3 independent experiments. **P = 0.03; *P = 0.08, paired t test. Numbers in the dot plots denote the percentages of 25D1.16-positive cells. (B) Left: Apo-OVA were incubated with BMDCs for 6 hours; colocalization of MHCI/OVA peptide complexes and lysosomes was examined by confocal microscopy. The images are representatives of 3 independent experiments with similar results. Right: colocalization of 25D1.16 with LAMP-1. Result is representative of 3 experiments. ****P < 0.001. Original magnification, ×400.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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