Disease relevance of IL7R

• Defective IL7R expression in T(-)B(+)NK(+) severe combined immunodeficiency [1].
• BACKGROUND: Interleukin (IL)-7 levels are increased in patients with human immunodeficiency virus type 1 (HIV-1)-associated lymphopenia; however, the effects of this on IL-7 receptor (IL-7R) expression, disease progression, and immune reconstitution remain unclear [2].
• CONCLUSIONS: Perturbations in the IL-7/IL-7R system were clearly associated with disease progression but did not reliably predict immune reconstitution [2].
• The communication between the epithelium and mucosal lymphocytes which is mediated via IL-7 and IL-7R may be involved in the modulation of the mucosal inflammation which occurs in bacterial infection [3].
• HIV-1 proteins may cause down-modulation of IL-7R expression, either by producing an insufficient number of molecules or by rapid decay of IL-7R on T cells [4].
• We describe allelic association of a polymorphism in the gene encoding the interleukin 7 receptor alpha chain (IL7R) as a significant risk factor for multiple sclerosis in four independent family-based or case-control data sets (overall P = 2.9 x 10(-7)) [5].

High impact information on IL7R

• We now demonstrate that defective IL7R expression causes T(-)B(+)NK(+) SCID, indicating that the T-cell, but not the NK-cell, defect in XSCID results from inactivation of IL-7Ralpha signalling [1].
• In addition, several cDNA clones were isolated that encode a secreted form of the human IL-7 receptor capable of binding IL-7 in solution [6].
• Impaired immunoglobulin gene rearrangement in mice lacking the IL-7 receptor [7].
• Interleukin-2 receptor gamma chain: a functional component of the interleukin-7 receptor [8].
• The observation that IL-2R gamma is a functional component of the IL-4 receptor, together with the finding that IL-2R gamma associates with the IL-7 receptor, begins to elucidate why deficiency of this common gamma chain (gamma c) has a profound effect on lymphoid function and development, as seen in X-linked severe combined immunodeficiency [9].

Chemical compound and disease context of IL7R

• Specifically, the key role of IL-7 in promoting T cell development has been substantiated by the identification of rare patients with T-B+ SCID who have a defect in the alpha subunit of the IL-7 receptor (IL7Ralpha) [10].
• Engagement of interleukin-7 receptor stimulates tyrosine phosphorylation, phosphoinositide turnover, and clonal proliferation of human T-lineage acute lymphoblastic leukemia cells [11].

Biological context of IL7R

• The four known IL7R promoter haplotypes were shown to have similar expression levels in healthy controls, but not in CPMS (P < 0.01, t test) [12].
• These results suggest that PI-3 kinase is involved in signal transduction via the IL-7R in human thymocytes [13].
• However, the exact mechanism whereby the IL-7 receptor (IL-7R) mediates these cell growth signals remains unknown [13].
• In response to IL-7 stimulation, Jak-3 phosphorylation was markedly reduced in both patient cells as well as in COS cells reconstituted with mutant IL-7R alpha [14].
• These results indicate that IL-7R alpha expression defines entry into a developmental stage characterized by upregulation of multiple lymphoid-associated genes and enhanced fitness for B-lymphoid differentiation [15].

Anatomical context of IL7R

• Indeed, complete gamma c deficiency like IL-7R alpha deficiency results in the arrest of T-cell but not B-cell development (T(-)B(+) SCID) [14].
• Expression of interleukin-7 receptor by lineage-negative human bone marrow progenitors with enhanced lymphoid proliferative potential and B-lineage differentiation capacity [15].
• In contrast to IL-7R alpha, loss of the stem cell factor receptor c-kit was associated with enhanced lymphoid clonogenic potential and increased B-lineage differentiation potential [15].
• One unexpected result was the high level of interleukin-7 receptor (IL-7R) gene expression in HS-27a stromal cells [16].
• The upregulation of the IL-7R occurs at the stage of the clonogenic common lymphoid progenitor, a recently identified population that can give rise to all lymphoid lineages (T, B and natural killer cells) at a single cell level [17].

Associations of IL7R with chemical compounds

• These data suggest that IL-7 may function to regulate the milieu of the microenvironment by modulating IL-6 secretion by the IL-7R-expressing stromal elements [16].
• Substitution of proline with serine in the extracellular portion of IL-7R alpha did not affect IL-7R alpha messenger RNA (mRNA) and protein expression, but severely compromised affinity to IL-7, resulting in defective signal transduction [14].
• The effects of IL-7 and cycloheximide on IL-7R expression by peripheral blood mononuclear cells were examined in vitro [2].
• In this study we describe abrogation of IL-7 driven proliferation and attenuated phosphotyrosine signaling by IL-7(143) (Trp-Ala) and IL-7(143) (Trp-His) in IL-7R expressing T and B leukemia cells [18].
• Alteration of a single tyrosine residue, Tyr410, in the IL-7R cytoplasmic domain to phenylalanine also prevents the inhibition of proliferation after antigen receptor assembly [19].

Physical interactions of IL7R

• On the basis of the RT-PCR reaction, molecular weight estimated in Western blot and IL-7 binding activity the identified endothelial IL-7 receptor was identical to the lymphocyte-type IL7-R [20].

Regulatory relationships of IL7R

• IL-7R alpha-expressing but not parental 32D cells proliferate in the presence of exogenous TSLP [21].
• Incubation of all seven patients' cells with IL7 induced coexpression to varying degrees of IL7-R and IL2-R [22].
• It is likely that higher TGF-beta concentrations do not inhibit lymphopoiesis by down-regulating IL-7 receptor expression, since this cytokine did not reduce IL-7R alpha or gamma c mRNA levels in normal B cell precursors [23].
• Compared to Flu, VV or EBV, HIV tetramer+ CD8 T cells expressed significantly lower levels of CD127, and this reduction was pervasive across all epitopes and alleles tested and over a wide range of viral loads and CD4 counts [24].

Other interactions of IL7R

• Untreated viremic patients showed a slight but significant decrease in CD127 expression on the surface of their CD4 lymphocytes [25].
• By contrast, CD127 expression was substantially altered on the surface of CD8 T lymphocytes taken from untreated viremic patients [25].
• Decreased phosphorylation of Jak3 kinase by IL-7W143A, IL-7W143P and IL-7W143H suggest that alterations in this region of the carboxyterminal region of IL-7 affects its interaction with the gammac subunit of the IL-7R [18].
• Surprisingly, in a substantial part of the myeloid lineage cells examined, an IL-2Rgamma+, IL-4R-, IL7R- configuration was noted that was, however, frequently associated with expression of IL-9R [26].
• Human TSLP is proposed to signal through a heterodimeric receptor complex that consists of a new member of the hemopoietin family termed human TSLP receptor and the IL-7R alpha-chain [27].

Analytical, diagnostic and therapeutic context of IL7R

• Activation of phosphatidylinositol-3 kinase by ligation of the interleukin-7 receptor on human thymocytes [13].
• Northern blot analysis confirmed the IL-7R RNA expression, and Western blots for the IL-7R protein detected both a full-length (90-kd) IL-7R and a smaller 30-kd fragment in both HS-27a cells and primary stromal cell cultures, whereas only the 90-kd receptor protein was detected in peripheral blood mononuclear cells [16].
• Bacterial invasion induced IL-7R expression in T84 assessed by a semi-quantitative reverse transcription-polymerase chain reaction technique and flow cytometry [3].
• Interleukin (IL)-7 and IL-7 receptor alpha-chain (CD127) levels were the same at all ages, as shown by ELISA, flow cytometry and real-time PCR [28].
• IL-7/IL-7 receptor system regulation following IL-2 immunotherapy in HIV-infected patients [29].

References