TAK1 is indispensable for development of T cells and prevention of colitis by the generation of regulatory T cells.
Transforming growth factor (TGF)-beta-activating kinase 1 (TAK1) is critical for Toll-like receptor- and tumor necrosis factor-mediated cellular responses. In B cells, TAK1 is essential for the activation of mitogen-activated protein kinases (MAPKs), but not nuclear factor-kappaB (NF-kappaB), in antigen receptor signaling. In this study, we generate T cell-specific TAK1-deficient (Lck(Cre/(+))Tak1(flox/flox)) mice and show that TAK1 is indispensable for the maintenance of peripheral CD4 and CD8 T cells. In thymocytes, TAK1 is essential for TCR-mediated activation of both NF-kappaB and MAPKs. Additionally, Lck(Cre/(+))Tak1(flox/flox) mice developed colitis as they aged. In these mice, accumulations of activated/memory T cells as well as B cells were observed. Development of regulatory T (Treg) cells in thymus was abrogated in Lck(Cre/(+))Tak1(flox/flox) mice, suggesting that the loss of Treg cells is the cause of the disease. Together, the results show that TAK1, by controlling the generation of central Treg cells, is important for preventing spontaneously developing colitis.
Sato
Shintaro
S
Akira Innate Immunity Project, Exploratory Research for Advanced Technology, Japan Science and Technology Agency, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
Sanjo
Hideki
H
Tsujimura
Tohru
T
Ninomiya-Tsuji
Jun
J
Yamamoto
Masahiro
M
Kawai
Taro
T
Takeuchi
Osamu
O
Akira
Shizuo
S
D000375:Aging / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D003092:Colitis / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000172:deficiency / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D013950:Thymus Gland / Q000276:immunology / Q000473:pathology; D000099151:MAP Kinase Kinase Kinase 7
D020930:MAP Kinase Kinase Kinases; D000099151:MAP Kinase Kinase Kinase 7