Development of colitis in signal transducers and activators of transcription 6-deficient T-cell receptor alpha-deficient mice: a potential role of signal transducers and activators of transcription 6-independent interleukin-4 signaling for the generation of Th2-biased pathological CD4+ betabetaT cells.
Forbidden CD4(+)betabeta T cells, which produce interleukin (IL)-4 predominantly, are a pathological subset in the development of colitis in T-cell receptor alpha chain (TCRalpha)-deficient mice. Stimulation of naive CD4(+) T cells with IL-4 induces Th2 development via the activation of signal transducers and activators of transcription (STAT) 6. In the present study, we had found that IL-4 enhanced the expression of STAT6 in CD4(+)betabeta T cells isolated from TCRalpha(-/-) mice with colitis, suggesting that the IL-4 signal in the CD4(+)betabeta T cells is mediated by STAT6. To further investigate the role of STAT6 in the development of colitis induced by TCRalpha deficiency, we generated double-deficient mice by crossing TCRalpha(-/-) mice and STAT6(-/-) mice. Surprisingly, STAT6 deficiency did not result in decreased severity of colitis in TCRalpha(-/-) mice. STAT6-deficient CD4(+)betabeta T cells produced IL-4 and intraperitoneal injection of anti-IL-4 monoclonal antibody in the nondiseased TCRalpha(-/-) and STAT6 double-deficient mice prevented the colitis formation, thus indicating that the cells differentiated into the Th2 phenotype have the ability to mediate the development of the colitis in the absence of STAT6.
Okuda
Yoshiko
Y
Department of Mucosal Immunology and Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
Takahashi
Ichiro
I
Kim
Jin-Kyung
JK
Ohta
Noriyuki
N
Iwatani
Kouichi
K
Iijima
Hideki
H
Kai
Yasuyuki
Y
Tamagawa
Hiroshi
H
Hiroi
Takachika
T
Kweon
Mi-Na
MN
Kawano
Sunao
S
Takeda
Kiyoshi
K
Akira
Sizuo
S
Sasaki
Yutaka
Y
Hori
Masatsugu
M
Kiyono
Hiroshi
H
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology*; D003092:Colitis / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control; D003106:Colon / Q000187:drug effects / Q000473:pathology; D003433:Crosses, Genetic; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000172:deficiency* / Q000235:genetics; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000502:physiology; D018418:Th2 Cells / Q000473:pathology*; D015534:Trans-Activators / Q000172:deficiency* / Q000235:genetics
D000911:Antibodies, Monoclonal; D016693:Receptors, Antigen, T-Cell, alpha-beta; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D015847:Interleukin-4