Suppression of Con A-induced hepatitis induction in ICOS-deficient mice.
Although there is growing evidence that NKT cells play an important role in various immune responses through the invariant T cell receptor, other cell surface molecules responsible for their function are not fully understood. Here we study the role of ICOS, the third member of the CD28 family of costimulatory receptors, in in vivo and in vitro NKT cell responses. To establish its in vivo role in systems dependent on NKT cells, we examined the development of Con A-induced hepatitis in ICOS knockout (ICOS(-/-)) mice. We demonstrated that hepatic injury in ICOS(-/-) mice was greatly suppressed as evidenced by the reduced elevation of serum transaminases, reduced apoptosis of hepatocytes and mild histopathological changes. In investigating the cause of this defect, we first found that the NKT cell population is significantly reduced in the liver and spleen of ICOS(-/-) mice. We made and analyzed mixed bone marrow chimera mice with bone marrow cells from ICOS(+/+) and ICOS(-/-) mice, and demonstrated that the defect in ICOS-mediated costimulation results in a significant defect in the development of NKT cells, especially of Valpha14i NKT cells, in the thymus. When we examined the function of residual NKT cells in ICOS(-/-) mice, we found that their cytokine production following stimulation with alpha-galactosylceramide (alpha-GalCer) was strongly impaired. Based on these findings, we propose that ICOS-mediated costimulation may play a critical role in both the development and the optimal function of NKT cells, and that defective ICOS-mediated costimulation may result in impaired Con A-induced hepatitis in ICOS(-/-) mice.
Watanabe
Shiho
S
Division of Immunobiology, Research Institute for Biological Sciences, Tokyo University of Science, 2669 Yamazaki, Noda, Chiba 278-0022, Japan.
Ohnuki
Kazunobu
K
Hara
Yasushi
Y
Ishida
Yasuo
Y
Ikarashi
Yoshinori
Y
Ogawa
Shuhei
S
Kishimoto
Hidehiro
H
Tanabe
Kazunari
K
Abe
Ryo
R
D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D002678:Chimera; D005260:Female; D005699:Galactosylceramides / Q000378:metabolism; D006505:Hepatitis / Q000276:immunology*; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein; D008213:Lymphocyte Activation; D018942:Macrolides / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
D000945:Antigens, Differentiation, T-Lymphocyte; D005699:Galactosylceramides; C556692:ICOS protein, human; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D018942:Macrolides; C036978:concanamycin A