Requirements of transcription factor Smad-dependent and -independent TGF-β signaling to control discrete T-cell functions.
TGF-β modulates immune response by suppressing non-regulatory T (Treg) function and promoting Treg function. The question of whether TGF-β achieves distinct effects on non-Treg and Treg cells through discrete signaling pathways remains outstanding. In this study, we investigated the requirements of Smad-dependent and -independent TGF-β signaling for T-cell function. Smad2 and Smad3 double deficiency in T cells led to lethal inflammatory disorder in mice. Non-Treg cells were spontaneously activated and produced effector cytokines in vivo on deletion of both Smad2 and Smad3. In addition, TGF-β failed to suppress T helper differentiation efficiently and to promote induced Treg generation of non-Treg cells lacking both Smad2 and Smad3, suggesting that Smad-dependent signaling is obligatory to mediate TGF-β function in non-Treg cells. Unexpectedly, however, the development, homeostasis, and function of Treg cells remained intact in the absence of Smad2 and Smad3, suggesting that the Smad-independent pathway is important for Treg function. Indeed, Treg-specific deletion of TGF-β-activated kinase 1 led to failed Treg homeostasis and lethal immune disorder in mice. Therefore, Smad-dependent and -independent TGF-β signaling discretely controls non-Treg and Treg function to modulate immune tolerance and immune homeostasis.
Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA.
Ai-Di
AD
Gu
Yunqi
Y
Wang
Lin
L
Lin
Song S
SS
Zhang
Yisong Y
YY
Wan
D000818:Animals; D017353:Gene Deletion; D006706:Homeostasis / Q000276:immunology; D007249:Inflammation / Q000473:pathology; D019426:Integrases / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D015398:Signal Transduction / Q000276:immunology*; D051899:Smad2 Protein / Q000172:deficiency / Q000378:metabolism*; D051900:Smad3 Protein / Q000172:deficiency / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
D019426:Integrases; D020930:MAP Kinase Kinase Kinases; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D000099151:MAP Kinase Kinase Kinase 7; C045073:Cre recombinase