CD4+ T-cell dysfunctions through the impaired lipid rafts ameliorate concanavalin A-induced hepatitis in sphingomyelin synthase 1-knockout mice.

Abstract

Membrane microdomains consisting of sphingomyelin (SM) and cholesterol appear to be important for signal transduction in T-cell activation. The present study was designed to elucidate the role of membrane SM in vivo and in vitro using sphingomyelin synthase 1 (SMS1) knock out (SMS1(-/-)) mice and Concanavalin A (ConA)-induced hepatitis. After establishing SMS1(-/-) mice, we investigated CD4+ T-cell functions including proliferation, cytokine production and signal transduction in vivo. We also examined severity of hepatitis, cytokine production in serum and liver after ConA injection at a dose of 20 mg kg(-1). CD4+ T cells from SMS1(-/-) mice showed severe deficiency of membrane SM and several profound defects compared with wild-type controls as follows: (i) cellular proliferation and production of IL-2 and IFN-γ by co-cross-linking of CD3 and CD4; (ii) tyrosine phosphorylation of LAT and its association with ZAP-70; (iii) clustering and co-localization of TCR with lipid rafts. Consistent with these impaired CD4+ T-cell functions in vitro, SMS1(-/-) mice showed decreased serum levels of IL-6 and IFN-γ by ConA injection, which renders SMS1(-/-) mice less sensitive to ConA-induced hepatitis. These results indicated that the deficiency of membrane SM caused the CD4+ T-cell dysfunction through impaired lipid raft function contributed to protection of ConA-induced liver injury, suggesting that the membrane SM is critical for full T-cell activation both in vitro and in vivo.

• Authors: Lingli Dong, Ken Watanabe, Mari Itoh, Cheng-Ri Huan, Xiao-Peng Tong, Takuji Nakamura, Miyuki Miki, Haruka Iwao, Akio Nakajima, Tomoyuki Sakai, Takafumi Kawanami, Toshioki Sawaki, Yasufumi Masaki, Toshihiro Fukushima, Yoshimasa Fujita, Masao Tanaka, Masato Yano, Toshiro Okazaki, Hisanori Umehara
• Journal: International immunology (Int Immunol) Vol. 24 Issue 5 Pg. 327-37 (May 2012) ISSN: 1460-2377 [Electronic] England
• PMID: 22345277 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Concanavalin A
• Sgms1 protein, mouse
• Transferases (Other Substituted Phosphate Groups)

Topics

• Animals
• CD4-Positive T-Lymphocytes (immunology, pathology)
• Concanavalin A (immunology)
• Hepatitis (immunology)
• Membrane Microdomains (pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Transferases (Other Substituted Phosphate Groups) (deficiency, immunology)