Apoptotic cells activate NKT cells through T cell Ig-like mucin-like-1 resulting in airway hyperreactivity.
T cell Ig-like mucin-like-1 (TIM-1) is an important asthma susceptibility gene, but the immunological mechanisms by which TIM-1 functions remain uncertain. TIM-1 is also a receptor for phosphatidylserine (PtdSer), an important marker of cells undergoing programmed cell death, or apoptosis. We now demonstrate that NKT cells constitutively express TIM-1 and become activated by apoptotic cells expressing PtdSer. TIM-1 recognition of PtdSer induced NKT cell activation, proliferation, and cytokine production. Moreover, the induction of apoptosis in airway epithelial cells activated pulmonary NKT cells and unexpectedly resulted in airway hyperreactivity, a cardinal feature of asthma, in an NKT cell-dependent and TIM-1-dependent fashion. These results suggest that TIM-1 serves as a pattern recognition receptor on NKT cells that senses PtdSer on apoptotic cells as a damage-associated molecular pattern. Furthermore, these results provide evidence for a novel innate pathway that results in airway hyperreactivity and may help to explain how TIM-1 and NKT cells regulate asthma.
Lee
Hyun-Hee
HH
Division of Immunology and Allergy, Department of Pediatrics, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
Meyer
Everett H
EH
Goya
Sho
S
Pichavant
Muriel
M
Kim
Hye Young
HY
Bu
Xia
X
Umetsu
Sarah E
SE
Jones
Jennifer C
JC
Savage
Paul B
PB
Iwakura
Yoichiro
Y
Casasnovas
Jose M
JM
Kaplan
Gerardo
G
Freeman
Gordon J
GJ
DeKruyff
Rosemarie H
RH
Umetsu
Dale T
DT
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D001249:Asthma / Q000276:immunology* / Q000378:metabolism; D016535:Bronchial Hyperreactivity / Q000276:immunology* / Q000378:metabolism; D002469:Cell Separation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D000072596:Hepatitis A Virus Cellular Receptor 1; D008213:Lymphocyte Activation / Q000276:immunology*; D008565:Membrane Proteins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000378:metabolism; D010718:Phosphatidylserines / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction
C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; D008565:Membrane Proteins; D010718:Phosphatidylserines