Generation of Mice with Conditionally Activated Transforming Growth Factor Beta Signaling Through the TβRI/ALK5 Receptor

We generated a transgenic mouse strain (LSL-T beta RI(CA)) containing a latent constitutively active TGF beta type I receptor (T beta RI/ALK5) by using a knock-in strategy into the X chromosome-linked hypoxanthine phosphoribosyl-transferase (Hprt) locus. Transgene expression, under the control of the ubiquitous CAG (human cytomegalovirus enhancer and chicken P-actin) promoter, is repressed by a floxed transcriptional Stop (LSL, Lox-Stop-Lox). In the presence of crerecombinase, the Stop is excised to allow T beta RI(CA) transgene expression. We showed that restricted expression of T beta RI(CA) in T lymphocytes efficiently activates TGFP signaling and rescues the T-cell autoimmune disorders of TGF beta RII conditional knockouts. Unexpectedly, our study reveals that TGFP signaling upregulation controls T-cell activation but does not impair their development or their peripheral homeostasis. In addition to the information provided on TGF beta effects on T-cell biology, LSL-T beta RI(CA) mouse constitutes an attractive tool to address the effect of TGFP signaling upregulation in any cell type expressing the cre-recombinase. genesis 46:724-731, 2008. Published 2008 Wiley-Liss, Inc.