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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 7

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 12

Apoptotic cell fragments in Mfge8–/– DCs persist in EEA-positive endosomes.

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Apoptotic cell fragments in Mfge8–/– DCs persist in EEA-positive endosom...
(A) PKH-labeled apoptotic cells were incubated with BMDCs for 6 (top) or 24 hours (bottom). The colocalization of apoptotic cells and EEA-1 plus early endosomes was visualized by confocal microscopy. Experiments with DAPI staining were analyzed using Zeiss 510 Meta confocal microscope and those without DAPI using Leica SP1 confocal microscope. Original magnification, ×400. (B) Colocalization of EEA-1 with all apoptotic cell material in WT, Mfge8–/–, and Mfge8–/– plus rMFG-E8 BMDCs at 6 and 24 hours after ingestion. Results are representative of 3 experiments. **P < 0.001.

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