TOB in T-Cell Signaling
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TOB in T-Cell Signaling
Efficient ligation of the TCR (T-Cell Receptor) by high-density Antigen can generate a productive T-Cell response and result in cytokine secretion and clonal expansion that 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 (Ref.1). Deregulation of T-Cell function, whether by defect or by excess, may result in dire consequences for us i.e., immunodeficiency and autoimmunity respectively. If the T-Cell response is too great 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 the T-Cells in quiescent and unresponsive state is an essential component of the balanced functioning of the immune system. Suboptimal cross-linking of the TCR by Antigen, which often happens under physiological conditions, is not sufficient to induce a productive immune response, but instead leads to T-Cell anergy. The quiescent state of unstimulated T-lymphocytes may be due to a lack of activation signals or because of the presence of inhibition signals. In contrast to primary unstimulated T-Cells, which can enter the cell cycle and clonally expand after Antigen-specific stimulation, anergic T-Cells do not proliferate. Instead, they remain in a state of long-term Antigen-specific unresponsiveness. TOB (Transducer of ERBB2)—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 (B-Cell Translocation Gene) anti-proliferative protein family (Ref.2). TOB expression is highest in unstimulated and anergic T-Cells, and is reduced in activated T-cells. Down-regulation of TOB is necessary for T-Cell activation (Ref.3).

Induction of productive T-Cell responses and T-Cell anergy is an active signaling process that requires protein tyrosine phosphorylation and Ca2+ (Calcium) mobilization. However, the biochemical signaling events, which predominate during induction of anergy, are very different from those that predominate during induction of productive T-Cell activation. These events result in increased expression of p27(KIP1) (Cyclin Dependent Kinase Inhibitor-p27), defective activation of CDK2 (Cyclin-Dependent Kinase-2), hypophosphorylation of Rb (Retinoblastoma) protein and blockade of the cell cycle in the G1 phase (Ref.1). TOB not only prevents T-Cell cycle progression but also blocks IL-2 (Interleukin-2) transcription through its association with SMADs : SMAD2 and SMAD4, which enhances SMAD binding on the IL-2 promoter. IL-2 is a cytokine that plays a key role in the activation and proliferation of T cells. In normal T-Cells, engagement of TCR-CD3 complexes leads to a membrane-proximal cascade of tyrosine phosphorylation events that ultimately lead to the activation of multiple pathways, including ERK (Extracellular Signal Regulated Kinase), JNK (c-Jun N-terminal Kinase), NF-KappaB (Nuclear Factor-KappaB) and NFAT (Nuclear Factor of Activated T-Cells) leading to the activation of the IL-2 gene promoter region subsequently followed by IL-2 gene transcription. Repression of IL-2 gene in T-Cells can be brought about by the interaction of TOB with SMAD proteins (Ref.4).

SMADs inhibit TCR-CD3 and CD28-mediated IL-2 gene transcription and this inhibitory effect is augmented by TOB as it enhances SMAD binding to the -105 negative regulatory element of the IL-2 promoter. SMADs mediate signals induced by TGF-Beta (Transforming Growth Factor-Beta). Binding of TGF-Beta to its Type II receptor (TGF-BetaRII) leads to recruitment of Type I receptor (TGF-BetaRI). The activated TGF-BetaRI then phosphorylates its downstream targets: SMAD2 and SMAD3. They form hetero-oligomeric complexes with SMAD4 and translocate to the nucleus. TOB interacts with the SMADs, enhancing their binding to the -105 negative regulatory element of the IL-2 promoter that represses IL-2 expression (Ref.4). In addition to its interaction with SMADs, TOB associates with CAF1 (Carbon Catabolite Repressor Protein (CCR4)-Associative Factor-1), a component of the CCR4 transcriptional regulatory complex (Ref.5). TOB actively blocks 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 (Cyclin-Dependent Kinase-2)—and promoting synthesis of a negative regulator of the cell cycle, p27(KIP1). Thus, expression of TOB inhibits T-Cell proliferation and transcription of cytokines and cyclins (Ref.4).

TOB inhibits T-Cell activation by increasing the threshold of T-Cell activation. Therefore, elimination of TOB will lower the threshold of T-Cell activation, allowing TCR-CD3 stimulation to fully activate T-Cells. TOB is down-regulated by CD3 signaling in the presence of CD28 costimulation, which reduces the threshold of TCR-CD3-mediated stimulation, thus suggesting that the mechanism of CD28 costimulation is the down-regulation of TOB expression. On the contrary, once expressed, TOB inhibits the process of costimulation of TCR signaling by CD28. Thus, the resting state of T cells could be an actively maintained gene program that must be repressed to observe T-Cell activation (Ref.1). Since T-Cells play various critical roles in orchestrating the immune responses, knowledge about TOB functions should lead to an of how the immune system could be better manipulated to overcome afflictions such as cancer, infection and autoimmune diseases (Ref.5).