TGF-β signaling in T cells: roles in lymphoid and epithelial neoplasia

Abstract

Transforming growth factor-b (TGF-b) plays an essential role in regulating the homeostasis of cells in the lymphoid lineage. TGF-b signaling is not required for normal thymopoiesis, but is essential for regulating the expansion, activation, and effector function of the mature CD4 þ and CD8 þ T cells in the peripheral lymphoid organs and target tissues. Recent studies in both mice and humans have elucidated an important and complex role for TGF-b in regulatory T-cell biology. Disruption of TGF-b signaling in T cells impairs the maintenance of regulatory T cells, results in the expansion of activated effector T cells, and is associated with the production of cytokines that have major effects on cells in their environment. While autoimmunity and inflammation are the principal phenotypes associated with the abrogation of TGF-b signaling in T cells in mice, emerging evidence now also directly links Smad-dependent TGF-b signaling in T cells to the suppression of epithelial neoplasia. The TGF-b receptor-activated Smad3 plays a critical role in mediating many of the inhibitory effects of TGF-b signaling in T cells, and has now been established as an important suppressor of leukemogenesis. These studies are increasing our awareness of the many complex mechanisms through which TGF-b signaling controls the pathogenesis of cancer.

Gfi-1 represses CDKN2B encoding p15 INK4B through interaction with Miz-1

“…Impaired TGF␤ signaling has been implicated in tumorigenesis, including hematopoietic and epithelial malignancies (34,39). Notably, p15 INK4B represents an important effector of TGF␤-induced growth arrest.…”

“…TGF␤ is an anti-mitogenic cytokine and impaired TGF␤ signaling has been implicated in tumorigenesis (33,34). Notably, p15 INK4B represents an important effector of the anti-growth activity of TGF␤ and is up-regulated by TGF␤.…”

Addition of the CD28 signaling domain to chimeric T-cell receptors enhances chimeric T-cell resistance to T regulatory cells

“…TGF-b inhibits the proliferation and effector function of T cells by inhibiting IL-2 production, but also affects cell-cyclerelated proteins and has additional less well-understood inhibitory actions. 33 The enhanced T-cell proliferation and cytokine expression mediated by the CD28 domain in the chimeric T cells evidently allows for a higher threshold for the effects of TGF-b inhibitory signaling, although it does not completely abrogate sensitivity to this agent.…”

Association of functional polymorphisms of the transforming growth factor B1 gene with survival and graft-versus-host disease after unrelated donor hematopoietic stem cell transplantation

“…7 Studies have shown that TGF-β1 can inhibit effector T-cell proliferation and activation and decrease Th1 and Th2 cell differentiation, while promoting differentiation of Th17 cells. 8,9 Moreover, TGF-β1 is essential for the proliferation of induced T regulatory (Treg) cells 10,11 and up-regulation of FOXP3 12 and plays a role in the immunosuppressive function of Treg due to cytokine secretion or membrane bound expression. 9,11,13 Several functional polymorphisms in TGFB1, the gene encoding for TGF-β1, have been identified, such as a single nucleotide polymorphism (SNP) at codon 10 (coding(c).29T>C, protein(p).L10P) and another at codon 25 (c.75G>C, p.A74P) of exon 1.…”