Disease relevance of Il2ra

• Recently, we identified a child born with a genetic deficiency of IL-2 receptor alpha (IL-2Ralpha, CD25) expression who had several clinical manifestations of primary biliary cirrhosis (PBC) [1].
• The failure of AICD observed with CD25 -/- T cells may explain the unexpected observation that deficiency of IL-2 or of the alpha- or beta-chain of the IL-2R results not in immunodeficiency, but in autoimmune disease [2].
• In summary, the CD3,25 BSMAB selectively targets activated CD25-expressing T cells and lymphomas although maintaining a low activation potential for unstimulated T cells, potentially advantageous properties that can be exploited for immunotherapy [3].
• SCID, RAG-2T, microMT and lambda 5T mutant mice do have normal, if not elevated numbers of pre-B-I cells but lack all CD25+ pre-B-II cells in their bone marrow [4].
• We recently characterized a CD4+ T cell population expressing the IL-2R alpha chain (CD25), producing IL-10 and resisting clonal deletion induced by viral superantigen (vSAG) encoded by mouse mammary tumor virus [MMTV(SW)] [5].

High impact information on Il2ra

• Unlike the IL-2R alpha chain, the IL-2R beta chain contains a large cytoplasmic domain that shows no obvious tyrosine kinase motif [6].
• The mechanism of induction of CD25 before T cell receptor rearrangement and the importance of this mechanism for T cell development are unknown [7].
• Functionally distinct NF-kappa B binding sites in the immunoglobulin kappa and IL-2 receptor alpha chain genes [8].
• We show that expression of Foxp3 is highly restricted to the subset alphabeta of T cells and, irrespective of CD25 expression, correlates with suppressor activity [9].
• In recombinase gene null pre-T cells, membrane and cytosolic active PKD both induced differentiation reminiscent of beta selection: downregulation of CD25 and upregulation of CD2 and CD5 [10].

Biological context of Il2ra

• The basis for IL-2-induced IL-2 receptor alpha chain gene regulation: importance of two widely separated IL-2 response elements [11].
• The addition of 100 nM rIL-2 to T cells activated by phorbol dibutyrate was able to induce a proliferative response, and under these conditions tyrosine phosphorylation of the 97-kDa protein, the transient increase in p56lck kinase activity, and specific mRNA for IL-2R alpha chain, c-myc, and cdc2 were detected [12].
• The IL-2-dependent upregulation of the IL-2 receptor alpha chain and proliferation were partially suppressed in the T cells of transgenic mice [13].
• Functional responses and apoptosis of CD25 (IL-2R alpha)-deficient T cells expressing a transgenic antigen receptor [2].
• To examine the contribution of IL-2 to these processes, we have bred a class II-restricted TCR transgene into mice deficient in the alpha-chain of the IL-2R, CD25 [2].

• Spleen cells from mice bearing progressive growing methylcholanthrene-induced syngenic tumours were deeply hyporeactive in response to T-cell mitogens. This hyporeactivity was associated with decreased ability to synthesize mRNA for the inducible 55,000 MW interleukin-2 receptor (IL-2R ) [14].

• The stimulation with Con A of spleen cells from newborn mice, in contrast to cells from adult animals, does not result in synthesis of mRNA for inducible 55,000 molecular weight (MW) IL-2 receptors (IL-2R/CD25). The failure of neonatal spleen cells to synthesize IL-2R mRNA is an intrinsic property of the cells themselves, and it is not due to activity of natural suppressor cells present in newborn animals [15] .

Anatomical context of Il2ra

• Unexpectedly, Il2(-/-) and Il2ra(-/-) T(reg) cells were fully able to suppress T cell proliferation in vitro [16].
• The levels of CD25 are significantly higher in developing Th2 cells than in developing Th1 cells during in vitro differentiation [17].
• Thus, CD25(+) and CD25(-) subpopulations could be characterized as regulatory T cells (Treg cells) and Th2 cells, respectively [18].
• Consistent with their ability to make IL-10, both CD25(+) and CD25(-)CD4(+) T cells from infected mice were able, when stimulated with egg Ag, to suppress IL-12 production by CD40 agonist-stimulated dendritic cells [18].
• Supporting the hypothesis that FTY720 directly affects functional activity of CD4(+)CD25(+) Treg, we measured a significant increase of CD25 and FoxP3 expression in isolated lamina propria CD4(+) T cells of FTY720-treated mice [19].

Associations of Il2ra with chemical compounds

• We previously reported that IL-7 maintains the viability and differentiation potential of CD25 (IL-2R p55) positive CD3-CD4-CD8- thymic pre-T cells in vitro [20].
• Tumor necrosis factor and its p55 and p75 receptors are not required for axonal lesion-induced microgliosis in mouse fascia dentata [21].
• Furthermore, topical FK506 profoundly impaired oxazolone-induced up-regulation of CD25 expression on CD4+ LNC and dramatically decreased hapten-induced expansion of I-A+/B220+ and I-A+/CD69+ LNC subsets [22].
• IL-2 initially binds a high mannose-type glycan and a specific peptide sequence of the IL-2 receptor alpha-subunit and sequentially forms a high affinity complex of IL-2.IL-2 receptor alpha-, beta-, and gamma-subunits [23].
• IL-2Ralpha (CD25) expression on activated cells was significantly reduced by epicatechin and cocoa extract in a dose-dependent manner, achieving the highest inhibition of about 50 % when flavonoids were added 2 h before stimulation [24].

Physical interactions of Il2ra

• Evidence suggests that STAT4 also facilitates binding of other factors to the CD25 promoter including c-Jun [25].

Regulatory relationships of Il2ra

• We have confirmed that F42A does not bind to the IL-2R alpha chain when expressed alone on MT-1 cells or in the presence of the large or small excess of IL-2R beta chains present on either YT-1 cells or forskolin-induced YT-1 cells, respectively [26].
• This membrane environment and the absence of CD25 promotes Jak3 independent signal transduction and induction of antiapoptotic mechanisms [27].
• The IL-2R alpha-chain was also shown to be induced on Th1 clones when they were stimulated with B cell APC in the presence of IL-12 [28].
• We observed that TGF-beta 1 was able to increase both the percentage of CD3-DN cells expressing IL-2R alpha chains and the expression of IL-2R alpha chain in these cells [29].
• STAT4 is required for interleukin-12-induced chromatin remodeling of the CD25 locus [25].

Other interactions of Il2ra

• Interleukin 2 signaling is believed to be critically involved in several aspects of CD25(+) CD4(+) regulatory T cell biology, such as intrathymic development, peripheral survival and suppressive function [30].
• 1-2% of adult mouse thymocytes express the T cell receptor alpha/beta (TCR-alpha/beta) together with the interleukin (IL) 2R beta (p70), but not the alpha (p 55) chain [31].
• In infected mice, two subpopulations of CD4(+) cells, separable by their expression of CD25, make IL-10 [18].
• Pre-treated CD8 T cells from both age groups also displayed a significant increase in activation-induced CD69 and CD25 expression, and produced significantly higher amounts of interleukin-2 and interferon-gamma in comparison to their untreated counterparts [32].
• High affinity IL-2R signalling in the context of CD25 and the microdomain environment is characterized by Jak3 activation [27].

Analytical, diagnostic and therapeutic context of Il2ra

• By adoptive transfer we show that repopulation of the spleen by CD25(high)Foxp3(+) cells results from the re-expression of CD25 on peripheral populations of CD25(-)Foxp3(+) but not from the conversion of peripheral Foxp3(-) cells [33].
• Northern blot analysis confirmed the accumulation of p55 specific mRNA and the absence of the IL 2 transcript [34].
• CD25 and Foxp3 expression was measured by real-time quantitative polymerase chain reaction [35].
• In this report, we utilize chromatin immunoprecipitation assays to analyze IL-12-stimulated and STAT4-dependent changes in chromatin remodeling of the CD25 gene [25].
• Although flow cytometry revealed that RyR blockade had little effect on activation-induced expression of the alpha chain (CD25) of the high affinity IL-2 receptor, the inhibitory effect of RyR antagonists could not be reversed by the addition of exogenous IL-2 at initiation of culture [36].

References