From inception to output, Tcf1 and Lef1 safeguard development of T cells and innate immune cells
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From inception to output, Tcf1 and Lef1 safeguard development of T cells and innate immune cells Farrah C. Steinke • Hai-Hui Xue
Ó Springer Science+Business Media New York 2014
Hai-Hui Xue
Farrah C. Steinke
Abstract Transcription factors have recurring roles during T cell development and activation. Tcf1 and Lef1 are known to be essential for early stages of thymocyte maturation. Recent research has revealed several novel aspects of their functionality. Tcf1 is induced at the very earliest step of specifying hematopoietic progenitors to the T cell lineage as a key target gene downstream of Notch activation. In addition to promoting maturation of T-lineage-committed thymocytes, Tcf1 functions as a tumor suppressor in developing thymocytes, and this is mediated, paradoxically, by restraining Lef1 expression. After positive selection, Tcf1 and Lef1 act together to direct CD4?CD8? double positive thymocytes to a CD4? T cell fate. Although not required for CD8? T cell differentiation, Tcf1 and Lef1 cooperate with Runx factors to achieve stable silencing of the Cd4 gene in CD8? T cells. Tcf1 is also found to have versatile roles in innate immune cells, which partly mirror its functions in mature T helper cells. Discrepancy in requirements of Tcf1/Lef1 and b-catenin in T cells has been a long-standing enigma. We will review other protein factors interacting with Tcf1 and Lef1 and discuss their regulatory roles independent of b-catenin. Keywords
Tcf1 Lef1 T cell development Innate lymphoid cells
Introduction T cell factor 1 (Tcf1) and lymphoid enhancer factor 1 (Lef1), encoded by Tcf7 and Lef1 genes, respectively, are members of the Tcf/Lef family transcription factors. Both Tcf1 and Lef1 are abundantly expressed in T-lineage lymphocytes and contain a highly conserved high mobility group (HMG) domain that binds directly to DNA [1–4]. It has been well established that Tcf1 and Lef1 are effector F. C. Steinke H.-H. Xue Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA F. C. Steinke H.-H. Xue Interdisciplinary Immunology Graduate Program, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA H.-H. Xue (&) 51 Newton Rd. BSB Rm. 3-772, Iowa City, IA 52242, USA e-mail: [email protected]
transcription factors of the canonical Wnt signaling pathway. In the absence of Wnt stimulation, Tcf1 and Lef1 are bound by the Groucho-related (Grg/Tle) corepressors, and the expression of Wnt target genes is therefore negatively regulated. A cytosolic b-catenin ‘‘destruction’’ complex is comprised of multiple components, including two scaffolding proteins, adenomatous polyposis coli (APC) and Axin, and two serine/threonine protein kinases, casein kinase 1 (CK1) and glycogen synthesis kinase 3b (GSK3b) [5]. These kinases phosphorylate a cluster of 4 Ser/Thr residues in the N-terminus of b-catenin, marking it for ubiquitination and proteasome-mediated degradation. Binding of Wnt ligands to their Frizzed (Fzd) receptors and low-density lipoprotein receptor-r
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