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

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

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 1

Increased frequency of CD62LloCD8 effector memory T cells in Mfge8–/– mice.

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Increased frequency of CD62LloCD8 effector memory T cells in Mfge8–/– mi...
(A) Splenic CD8+ and CD4+ T cells from 4- or 12-month-old WT or Mfge8–/– mice were analyzed for the expression of CD44 and CD62L by flow cytometry. Representative of 4–12 mice in each group. The number in each quadrant shows the percentage of each population. (B) Summary of the ratios between CD62Llo and CD62LhiCD44+CD8+ T cell population in either WT or Mfge8–/– mice at different ages. *P = 0.02 (C) The ratios between CD4+ and CD8+ T cells in either WT or Mfge8–/– mice at different ages. *P = 0.02. (D) Splenic CD8+ T cells were negatively selected from 9-month-old WT or Mfge8–/– mice (n = 6) and 1 × 105 T cells stimulated with plate-bound anti-CD3 alone (1 μg/ml) or anti-CD3 plus anti-CD28 (1 μg/ml) for 3 days. The levels of IFN-γ and IL-2 in the supernatant were evaluated by ELISA. **P = 0.01.