title: Apoptotic cells activate NKT cells through T cell Ig-like mucin-like-1 resulting in airway hyperreactivity.
abstract: 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.
authors.affiliation: Division of Immunology and Allergy, Department of Pediatrics, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Hyun-Hee
authors.initials: HH
authors.lastname: Lee
authors.forename: Everett H
authors.initials: EH
authors.lastname: Meyer
authors.forename: Sho
authors.initials: S
authors.lastname: Goya
authors.forename: Muriel
authors.initials: M
authors.lastname: Pichavant
authors.forename: Hye Young
authors.initials: HY
authors.lastname: Kim
authors.forename: Xia
authors.initials: X
authors.lastname: Bu
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Umetsu
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Jones
authors.forename: Paul B
authors.initials: PB
authors.lastname: Savage
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Jose M
authors.initials: JM
authors.lastname: Casasnovas
authors.forename: Gerardo
authors.initials: G
authors.lastname: Kaplan
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: Rosemarie H
authors.initials: RH
authors.lastname: DeKruyff
authors.forename: Dale T
authors.initials: DT
authors.lastname: Umetsu
mesh_terms: 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
chemical_list: C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; D008565:Membrane Proteins; D010718:Phosphatidylserines