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IL-2 Gene Expression in Activated and Quiescent T-Cells
IL-2 (Interleukin-2) is a biological response modifier (cytokine), which stimulates 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 powerful immunoregulatory lymphokine that was originally described as "T-cell growth factor" and is secreted primarily by antigen-activated T-cells . Human IL-2 is a 133-amino acid polypeptide with a molecular mass of 15-18 kDa. In an autocrine fashion, the antigen-primed THC (T Helper Cell) secretes IL-2, stimulating itself as well as other neighboring antigen-primed T-cells to proliferate (T-cell activation and proliferation). Growing T-cells in long-term culture require IL-2 as a growth factor, and this cytokine is crucial for achieving T-cell–mediated immunity and thus regulation of the immune response .
In normal T-cells, engagement of TCR (T-cell receptor)-CD3 complexes, costimulation by CD28, and recruitment of LAT (Linker of Activated T-Cells) 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 expression . Since IL-2 gene expression in T-cells plays various critical roles in orchestrating the immune responses, deregulation of T-Cell function, whether by defect or by excess, results in dire consequences for the organism (i.e., immunodeficiency and autoimmunity) . If the T-cell response is too great, it will culminate in excessive expression of IL-2, resulting in hyperactivation of immune response, that may give rise to autoimmune disorders or tissue injury. Therefore, regulation of T-cell activation and maintenance of the T-cells in a 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 IL-2 gene expression, and thus fails to induce a productive immune response, instead leading to T-cell quiescence .
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, termed as T-cell anergy. The quiescent state and the anergic state both result because of defective IL-2 gene expression. In quiescent T-cells, the activation signals (antigens) are either absent or are insufficient to trigger a productive immune response. Presence of inhibition signals also gives rise to quiescence and anergy [2,4]. The activation signals are not sufficient to trigger activation of the multiple pathways—including ERK, JNK, NF-KappaB, and NFAT—that usually lead to the activation of the IL-2 gene promoter region. Therefore, IL-2 gene transcription is hindered. On the other hand, the ERK, JNK, NF-KappaB, and NFAT pathways are inhibited by the presence of inhibitory substances, both in anergic and quiescent states. TOB (Transducer of ERBB2), a negative regulator of IL-2 transcription and T-cell proliferation, 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 . Its expression is highest in unstimulated and anergic T-cells, and is reduced in activated T-cells. Once expressed, TOB inhibits the process of costimulation of TCR signaling by CD28, and thus, repression of pathways, that normally lead to the IL-2 expression. In activated T-cells, expression of TOB is not normally observed. Otherwise, down-regulation of TOB is necessary for T-cell activation. Repression of IL-2 gene by TOB is brought about by the interaction of TOB with SMAD proteins. TOB inhibits TCR-CD3 and CD28–mediated IL-2 gene transcription by augmenting the inhibitory effect of the SMAD proteins. TOB enhances SMAD binding to the -105 negative regulatory element of the IL-2 promoter. In T-Cells, SMADs mediate signals induced by TGF-Beta (Transforming Growth Factor-Beta) through its receptors: TGF-BetaRII and TGF-BetaRI. The activated TGF-BetaRs phosphorylate the downstream targets SMAD2 and SMAD3, which form hetero-oligomeric complexes with SMAD4 and translocate to the nucleus. The SMAD complex downregulates IL-2 gene expression by binding to the -105 negative regulatory element of the IL-2 Promoter. TOB enhances the binding of the SMADs to the -105 negative regulatory element of the IL-2 promoter that represses IL-2 expression . Since IL-2 plays various critical roles in orchestrating the immune responses, a complete knowledge about its expression and repression would lead to an understanding of how the immune system could be better manipulated to overcome afflictions such as cancer, infection, and autoimmune diseases. Not only is it produced by mature T lymphocytes on stimulation, but also constitutively by certain T-cell lymphoma cell lines. IL-2 is the major tool in cytokine immunotherapy, in which prevention or reduction of disease progression is achieved through stimulation of cell-mediated immunity (i.e., immune reconstitution) by administration of exogenous T helper cell cytokines. IL-2 has been used successfully to manage several human cancers (metastatic melanoma, acute myelogenous leukemia, and metastatic renal cell carcinoma) and has recently been shown to be effective at improving immune responses in patients with HIV1 (Human Immunodeficiency Virus Type-1) disease .
- Osinalde N, Moss H, Arrizabalaga O, et al. (2011) Interleukin-2 signaling pathway analysis by quantitative phosphoproteomics. J Proteomics 75(1):177-91. Epub 2011 Jun 23.
- Villarino AV, Tato CM, Stumhofer JS, et al. (2007) Helper T cell IL-2 production is limited by negative feedback and STAT-dependent cytokine signals. J Exp Med 204(1):65-71. Epub 2007 Jan 16.
- Jerome KR (2008) Viral modulation of T-cell receptor signaling. J Virol 82(9):4194-204. Epub 2008 Feb 20. Review. No abstract available.
- Sprent J, Surh CD (2011) Normal T cell homeostasis: the conversion of naive cells into memory-phenotype cells. Nat Immunol 12(6):478-84. Review.
- Cooper LJ, Topp MS, Pinzon C, et al. (2004) Enhanced transgene expression in quiescent and activated human CD8+ T cells. Hum Gene Ther 15(7):648-58.
- Tzachanis D, Boussiotis VA (2009) Tob, a member of the APRO family, regulates immunological quiescence and tumor suppression. Cell Cycle 8(7):1019-25. Epub 2009 Apr 30. Review.
- Dix RD, Cousins SW (2004) Interleukin-2 immunotherapy and AIDS-related cytomegalovirus retinitis. Curr HIV Res 2(4):333-42. Review.
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