IL-2 Gene Expression in Activated and Quiescent T-Cells Pathway

Overview of IL-2 Gene Expression in Activated and Quiescent T-Cells Pathway

Interleukin-2 (IL-2) is a biological response modifier (cytokine) that promotes the growth, proliferation, and subsequent differentiation of disease-fighting blood cells such as T-Cells, B-Cells, NK (Natural Killer) cells, monocytes, macrophages, and oligodendrocytes. It is a potent immunoregulatory lymphokine originally referred to as "T-Cell growth factor" that is primarily secreted by Antigen-Activated T Cells (Ref.1). Human interleukin-2 (IL-2) is a 133-amino acid polypeptide with a molecular weight of 15-18 kDa. The Antigen-primed THC (T Helper Cell) secretes IL-2 in an autocrine manner, stimulating both itself and neighboring Antigen-primed T Cells to proliferate (T-Cell activation and proliferation).

In normal T-Cells, engagement of TCR-CD3 complexes, costimulation by CD28, and recruitment of LAT (Linker of Activated T-Cells) initiates a membrane-proximal cascade of tyrosine phosphorylation events that ultimately results in the activation of multiple pathways, including ERK (Extracellular Signal Regulated Kinase), JNK (c-Jun N-terminal Kinase). Given the critical role of IL-2 gene expression in orchestrating immune responses, deregulation of T-Cell function, whether due to a defect or an excess, has dire consequences for the organism, including immunodeficiency and autoimmunity . If the T-Cell response is excessive, it will result in excessive IL-2 expression, which will result in hyperactivation of the immune system, which may result in autoimmune disorders or tissue injury. Thus, regulation of T-Cell activation and maintenance of T-Cells in a quiescent and unresponsive state is critical for the immune system to function properly. Suboptimal cross-linking of the TCR by antigen, which frequently occurs under physiological conditions, is insufficient to induce IL-2 gene expression and thus does not result in a productive immune response, but rather in T-Cell quiescence.

Unstimulated T-lymphocytes may be quiescent due to a lack of activation signals or the presence of inhibitory signals. Unlike primary unstimulated T cells, which can enter the cell cycle and clonally expand in response to antigen stimulation, anergic T cells do not proliferate. Rather than that, they persist in a state of long-term antigen-specific inactivity, referred to as T-Cell anergy. Both the quiescent and anergic states are caused by abnormal IL-2 gene expression.

The activation signals (Antigens) in quiescent T-Cells are either absent or insufficient to initiate a productive immune response. Additionally, the presence of inhibitory signals results in quiescence and anergy (Ref.2 & 4). The activation signals alone are insufficient to activate the multiple pathways involved in the activation of the IL-2 gene promoter region, including ERK, JNK, NF-KappaB, and NFAT. As a result, transcription of the IL-2 gene is inhibited. On the other hand, inhibitory substances inhibit the ERK, JNK, NF-KappaB, and NFAT pathways in both anergic and quiescent states. TOB (Transducer of ERBB2), a negative regulator of IL-2 transcription and T-cell proliferation, is expressed constitutively in unstimulated peripheral blood T lymphocytes and selectively in anergic T lymphocytes.

TOB is a member of the anti-proliferative TOB and BTG (B-Cell Translocation Gene) protein families (Ref.5). It is expressed at a maximum level in unstimulated and anergic T-Cells and at a minimum level in activated T-Cells. Once expressed, TOB inhibits CD28-mediated costimulation of TCR signaling, thereby repressing the pathways that normally result in the expression of IL-2. Normally, TOB expression is not observed in activated T cells. Otherwise, T-Cell activation requires down-regulation of TOB. The interaction of TOB with SMAD proteins results in the repression of the IL-2 gene. TOB enhances the inhibitory effect of SMAD proteins on TCR-CD3 and CD28–mediated IL-2 gene transcription. TOB increases SMAD binding to the IL-2 promoter's -105 negative regulatory element.