T and B cell hyperactivity and autoimmunity associated with niche-specific defects in apoptotic body clearance in TIM-4-deficient mice.
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 do not 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.
Rodriguez-Manzanet
Roselynn
R
Department of Neurology, Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Harvard Institutes of Medicine, Boston, MA 02115, USA.
Sanjuan
Miguel A
MA
Wu
Henry Y
HY
Quintana
Francisco J
FJ
Xiao
Sheng
S
Anderson
Ana C
AC
Weiner
Howard L
HL
Green
Douglas R
DR
Kuchroo
Vijay K
VK
D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000276:immunology; D017209:Apoptosis / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002451:Cell Compartmentation; D005260:Female; D008213:Lymphocyte Activation / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010587:Phagocytosis / Q000276:immunology; D010641:Phenotype; D011995:Recombination, Genetic / Q000235:genetics; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology
D000974:Antibodies, Antinuclear; D008565:Membrane Proteins; C500399:TIM-4 protein, mouse