Antiproliferative Role of TOB in T Cell Signaling

Efficient ligation of the TCR by high-density antigens can generate a productive T cell response resulting in cytokine secretion and clonal expansion, and is crucial for an optimal immune response. TCR stimulation may provoke different cell responses (proliferation, anergy to subsequent stimuli, cell death) in mature circulating T cells. However, if the T cell response is excessive and activation of unstimulated cells and self-responsive cells is not suppressed, then it may give rise to autoimmune disorders or tissue injury. Therefore, regulation of T cell activation and maintenance of T cells in a quiescent and unresponsive state is an essential component of the balanced functioning of the immune system. Such anergic T cells do not proliferate. Instead, they remain in a state of long term antigen specific unresponsiveness. Transducer of ERBB2 (TOB), a negative regulator of T cell proliferation and cytokine transcription, is constitutively expressed in unstimulated peripheral blood T lymphocytes and selectively expressed in anergic T cells. TOB is a member of the TOB and BTG anti-proliferative protein family. Its expression is highest in unstimulated and anergic T cells. Down regulation of TOB is necessary for T cell activation.TOB mediates its antiproliferative role in T cell signaling by preventing cell cycle progression, blocking IL-2 transcription through its association with SMADs, and suppression of IL-2 translation. SMADs mediate signals induced by TGF-β. Binding of TGF-β to its type II receptor leads to recruitment of its type I receptor. Activated TGF-βRI then phosphorylates its downstream targets: SMAD2 and SMAD3. They form hetero-oligomeric complexes with SMAD4 and translocate to the nucleus where they associate with TOB, enhancing their binding to the -105 negative regulatory element of the IL-2 promoter that represses IL-2 expression. TOB is also involved in the regulation of IL-2 at the translational level: It has been shown to abrogate PABP4 enhanced translation of IL-2 mRNA by binding to PABP4. TOB has also been found to actively block the cell cycle progression of T cells by reducing synthesis of positive regulators of the cell cycle including Cyclin E, Cyclin A, Cyclin D1 and CDK2 and promoting synthesis of a negative regulator of the cell cycle, p27(KIP1). ERK phosphorylation of TOB negatively regulates its anti-proliferative function. Thus, expression of TOB inhibits T cell proliferation and transcription of cytokines and cyclins.TOB inhibits T cell activation by increasing the threshold of T cell activation. Elimination of TOB will lower this threshold of activation, allowing TCR-CD3 stimulation to fully activate T cells. Thus, the resting state of T cells could be an actively maintained gene program that must be repressed to observe T cell activation. (Upgraded 01/2020)