Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 19, Pages 8706-8711Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0910359107
Keywords
phosphatidylserine receptor; phagocytosis; autoantibody; apoptosis
Categories
Funding
- National Multiple Sclerosis Society [RG3996, RG2571D9]
- National Institutes of Health [NS045973, NS035685, NS030843, AI139671, AI045757, NS038037, AI044828]
- National Institute of Neurological Disorders and Stroke [NS056503]
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TIM-4, a member of the TIM family expressed on antigen-presenting cells, binds to phosphatidylserine exposed on the surface of apoptotic bodies. However, the significance of this interaction in vivo remains unknown because other receptors have been implicated in the clearance of apoptotic bodies and could compensate for the TIM-4 deficiency in vivo. In this study, we describe the generation of TIM-4-deficient mice and address whether TIM-4 serves a unique function in vivo. We show that TIM-4(-/-) peritoneal macrophages and B-1 cells donot efficiently engulf apoptotic bodies in vitro, or clear apoptotic bodies in vivo. TIM-4-deficient mice have hyperactive T and B cells, elevated levels of serum Ig, and develop antibodies to double-stranded DNA. Taken together, we show that TIM-4 is critical for the clearance of apoptotic bodies in vivo, and that lack of TIM-4 results in aberrant persistence of apoptotic bodies leading to dysregulated lymphocyte activation and signs of systemic autoimmunity.
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