Linkage analysis of the genetic determinants of T-cell IL-4 secretion, and identification of Flj20274 as a putative candidate gene

Choi, P.; D, Xanthaki; Rose, S.J.; Haywood, M; Reiser, Hans; Morley, Bernard J

doi:10.1038/sj.gene.6364192

Cited by 11 publications

(13 citation statements)

References 32 publications

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“…In addition, genetic variation in Il4ra has been shown to affect both IL-4-induced CD4 + T lymphocyte proliferation (59) and airway hyperresponsiveness in mice (59,60), indicating that the quantitative trait gene underlying this locus may be Il4ra. Indeed, in vitro T cell IL-4 production has been identified by several studies (61)(62)(63) to map to the same chromosome 7 locus as that identified in this study. Finally, polymorphisms in the priority candidate gene IL-21 receptor (Il21r) may have affected the pulmonary CD3 + counts in the B6 and BALB strains, as its ligand IL-21 functions to enhance T cell proliferation (64) and a Th2 differentiation (65), whereas Il21r-deficient mice demonstrate reduced levels of airway hyperresponsiveness to challenge (65).…”

Section: Discussionmentioning

confidence: 65%

Strain-Dependent Airway Hyperresponsiveness and a Chromosome 7 Locus of Elevated Lymphocyte Numbers in Cystic Fibrosis Transmembrane Conductance Regulator-Deficient Mice

Bazett

Stefanov

Paun

et al. 2012

The Journal of Immunology

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We previously observed the lungs of naive BALB/cJ Cftrtm1UNC mice to have greater numbers of lymphocytes, by immunohistochemical staining, than did BALB wild type littermates or C57BL/6J Cftrtm1UNC mice. In the present study, we initially investigated whether this mutation in Cftr alters the adaptive immunity phenotype by measuring the lymphocyte populations in the lungs and spleens by FACS and by evaluating CD3-stimulated cytokine secretion, proliferation, and apoptosis responses. Next, we assessed a potential influence of this lymphocyte phenotype on lung function through airway resistance measures. Finally, we mapped the phenotype of pulmonary lymphocyte counts in BALB × C57BL/6J F2 Cftrtm1UNC mice and reviewed positional candidate genes. By FACS analysis, both the lungs and spleens of BALB Cftrtm1UNC mice had more CD3+ (both CD4+ and CD8+) cells than did littermates or C57BL/6J Cftrtm1UNC mice. Cftrtm1UNC and littermate mice of either strain did not differ in anti-CD3–stimulated apoptosis or proliferation levels. Lymphocytes from BALB Cftrtm1UNC mice produced more IL-4 and IL-5 and reduced levels of IFN-γ than did littermates, whereas lymphocytes from C57BL/6J Cftrtm1UNC mice demonstrated increased Il-17 secretion. BALB Cftrtm1UNC mice presented an enhanced airway hyperresponsiveness to methacholine challenge compared with littermates and C57BL/6J Cftrtm1UNC mice. A chromosome 7 locus was identified to be linked to lymphocyte numbers, and genetic evaluation of the interval suggests Itgal and Il4ra as candidate genes for this trait. We conclude that the pulmonary phenotype of BALB Cftrtm1UNC mice includes airway hyperresponsiveness and increased lymphocyte numbers, with the latter trait being influenced by a chromosome 7 locus.

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Section: Discussionmentioning

confidence: 65%

Strain-Dependent Airway Hyperresponsiveness and a Chromosome 7 Locus of Elevated Lymphocyte Numbers in Cystic Fibrosis Transmembrane Conductance Regulator-Deficient Mice

Bazett

Stefanov

Paun

et al. 2012

The Journal of Immunology

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“…Congenic mapping has determined genetic trait loci on mouse chromosomes 5, 11, 12, 14, 15, 16, 17, 18, and 19 which impact Th2 bias, but the specific underlying determinants defined by the genetic loci are not known in most instances [84–87]. On chromosome 16, Dicer1.2, also known as Mina, acts as an IL-4 repressor.…”

Section: Detailed Review Of Innate and Adaptive Immunity With An Emphmentioning

confidence: 99%

T Helper Cell Polarization in Healthy People: Implications for Cardiovascular Disease

Olson

Sallam

Doyle

et al. 2013

J. of Cardiovasc. Trans. Res.

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Atherosclerosis is a chronic inflammatory disease characterized by T lymphocyte infiltration into the atherosclerotic plaque. Assessments of T cell subtypes have demonstrated a predominance of CD4+ T helper (Th) cells, implicated Th1 and Th17 immunity in both human and mouse atherogenesis, and provided some evidence suggesting protective roles of Th2 and T regulatory cells. Observations that certain inbred mouse strains have an inherent T helper bias suggests a genetic predisposition toward developing a particular T helper phenotype. This review summarizes our current understanding of mechanisms of antigen processing for major histocompatibility complex (MHC) molecules, describes the different T helper cell subsets and their roles in atherosclerosis, and discusses mechanisms of genetic predisposition toward Th1/Th2 bias in mice. We also present data from our laboratory demonstrating inherent Th1/Th2 phenotypes in apparently healthy human volunteers that are stable over time, and discuss the potential implications for cardiovascular disease.

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“…Genetic approaches to dissect T H 2-bias have yielded numerous quantitative trait loci (QTL) spread across mouse chromosomes 5, 12, 14 15, 16, 17, 18 and 19 (refs. 14, 26–29) and a single discrete genetic locus on chromosome 11 (refs. 24, 25).…”

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confidence: 99%

Mina, an Il4 repressor, controls T helper type 2 bias

et al. 2009

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T helper-2 (T H 2)-bias, the propensity of naive CD4 + T cells to differentiate into interleukin 4 (IL-4) secreting T H 2 cells, is a genetic trait impacting infectious, autoimmune and allergic disease susceptibility. T H 2-bias correlates with the amount of IL-4 initially secreted by newly activated T H cells that feeds back positively through the IL-4R-STAT6-GATA3 pathway to drive T H 2 development. Here, we identify Mina, a JmjC family member, as a genetic determinant of T H 2-bias. Mina specifically bound to and repressed the Il4 promoter. Mina overexpression in transgenic mice impaired Il4 expression, while its knockdown in primary CD4 + T cells led to Il4 derepression. Together, these findings provide mechanistic insight into an Il4 regulatory pathway controlling T H differentiation and genetic variation in T H 2-bias. Naive CD4 + T cells are multipotent sentinels of the immune system, poised to respond to instructive signals from antigen-presenting cells by differentiating into distinct effector cell lineages. These include T helper (T H ) 1 and T H 2 cells, differentially adapted for the control, respectively, of intra-and extracellular pathogens, in part via developmentally acquired potential for high expression of distinct cytokine genes 1 . Dysregulated CD4 + T cell development can promote susceptibility to infectious, autoimmune and allergic disease [2][3][4][5][6][7][8][9] .Interleukin 4 (IL-4) [http://www.signaling-gateway.org/molecule/query?afcsid=A001262], the canonical T H 2 effector cytokine, is also a critical developmental determinant, promoting Accession codesThe microarray data are deposited in RCAI RefDIC (URL: http://refdic.rcai.riken.jp/welcome.cgi) 50 under the following accession codes: RMSPTB007001 and RMSPTB008001. 11,12 to promote the differentiation of T H 2 cells possessing the capacity to secrete copious amounts of IL-4 10, 13-18 . Thus, regulation of autocrine IL-4 expression by activated T H cells is a key control point in T helper cell lineage commitment. Nonetheless, the molecular mechanism underlying this regulation is incompletely understood. Author contributions NIH Public AccessT H 2-bias is a complex genetic trait characterizing variation in the propensity of naive T H cells to differentiate into T H 2 (as opposed to T H 1) cells. T H 2-bias, measured experimentally as the amount of IL-4 produced by effector CD4 + T cells differentiated in vitro from naive T H cells activated under 'neutral' conditions (no exogenous cytokines added, except IL-2, and cultured without cytokine-specific antibodies), varies over 50-fold from the highproducer phenotype of BALB/c mice to the low-producer phenotype of B10.D2 mice and correlates with susceptibility to T H 2-dependent diseases such as bronchial asthma and leishmaniasis [14][15][16][19][20][21][22] . Various cellular mechanisms have been suggested as the basis for T H 2-bias, including variation in the sensitivity to prostaglandin 2 (PGE 2 )-dependent inhibition of interferon-γ (IFN-γ) production 23 , the timing of IL-1...

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Linkage analysis of the genetic determinants of T-cell IL-4 secretion, and identification of Flj20274 as a putative candidate gene

Cited by 11 publications

References 32 publications

Strain-Dependent Airway Hyperresponsiveness and a Chromosome 7 Locus of Elevated Lymphocyte Numbers in Cystic Fibrosis Transmembrane Conductance Regulator-Deficient Mice

Strain-Dependent Airway Hyperresponsiveness and a Chromosome 7 Locus of Elevated Lymphocyte Numbers in Cystic Fibrosis Transmembrane Conductance Regulator-Deficient Mice

T Helper Cell Polarization in Healthy People: Implications for Cardiovascular Disease

Mina, an Il4 repressor, controls T helper type 2 bias

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