TIM-1 and TIM-4 glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells.
The T cell immunoglobulin mucin (TIM) proteins regulate T cell activation and tolerance. Here we showed that TIM-4 is expressed on human and mouse macrophages and dendritic cells, and both TIM-4 and TIM-1 specifically bound phosphatidylserine (PS) on the surface of apoptotic cells but not any other phospholipid tested. TIM-4(+) peritoneal macrophages, TIM-1(+) kidney cells, and TIM-4- or TIM-1-transfected cells efficiently phagocytosed apoptotic cells, and phagocytosis could be blocked by TIM-4 or TIM-1 monoclonal antibodies. Mutations in the unique cavity of TIM-4 eliminated PS binding and phagocytosis. TIM-4 mAbs that blocked PS binding and phagocytosis mapped to epitopes in this binding cavity. These results show that TIM-4 and TIM-1 are immunologically restricted members of the group of receptors whose recognition of PS is critical for the efficient clearance of apoptotic cells and prevention of autoimmunity.
Kobayashi
Norimoto
N
Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Harvard Medical School, Boston, MA 02115, USA.
Karisola
Piia
P
Peña-Cruz
Victor
V
Dorfman
David M
DM
Jinushi
Masahisa
M
Umetsu
Sarah E
SE
Butte
Manish J
MJ
Nagumo
Haruo
H
Chernova
Irene
I
Zhu
Baogong
B
Sharpe
Arlene H
AH
Ito
Susumu
S
Dranoff
Glenn
G
Kaplan
Gerardo G
GG
Casasnovas
Jose M
JM
Umetsu
Dale T
DT
Dekruyff
Rosemarie H
RH
Freeman
Gordon J
GJ
D000818:Animals; D017209:Apoptosis; D003713:Dendritic Cells / Q000378:metabolism; D000072596:Hepatitis A Virus Cellular Receptor 1; D006801:Humans; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D010587:Phagocytosis; D010718:Phosphatidylserines / Q000737:chemistry / Q000378:metabolism*; D011991:Receptors, Virus / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology
C491143:HAVCR1 protein, human; C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D010718:Phosphatidylserines; D011991:Receptors, Virus; C500399:TIM-4 protein, mouse; C512411:TIMD4 protein, human