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BMC Immunology
Published in: BMC Immunology 1/2012

Open Access 01-12-2012 | Research article

A novel splice variant of folate receptor 4 predominantly expressed in regulatory T cells

Authors: Yi Tian, Guoqiang Wu, Jun-Chao Xing, Jun Tang, Yi Zhang, Ze-Min Huang, Zheng-Cai Jia, Ren Zhao, Zhi-Qiang Tian, Shu-Feng Wang, Xiao-Ling Chen, Li Wang, Yu-Zhang Wu, Bing Ni

Published in: BMC Immunology | Issue 1/2012

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Abstract

Background

Regulatory T cells (Tregs) are required for proper maintenance of immunological self-tolerance and immune homeostasis. Folate receptor 4 (FR4) is expressed at high levels in transforming growth factor-beta (TGF-β)-induced Tregs and natural Tregs. Moreover, antibody-mediated targeting of FR4 is sufficient to mediate Treg depletion.

Results

In this study, we describe a novel FR4 transcript variant, FR4D3, in which exon 3 is deleted. The mRNA of FR4D3 encodes a FR4 variant truncated by 189 bp. FR4D3 was found to be predominantly expressed in CD4+CD25+ Treg cells. Overexpression of FR4D3 in CD4+CD25+ Treg cells in vitro stimulated proliferation, which may modulate the ability of these cells to bind and incorporate folic acid.

Conclusions

Our results suggested that high levels of FR4D3 may be critical to support the substantial proliferative capacity of Treg cells.
Appendix
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Literature
1.
Shen F, Ross JF, Wang X, Ratnam M: Identification of a novel folate receptor, a truncated receptor, and receptor type beta in hematopoietic cells: cDNA cloning, expression, immunoreactivity, and tissue specificity. Biochemistry. 1994, 33 (5): 1209-1215. 10.1021/bi00171a021.PubMedCrossRef
2.
Antony AC: Folate receptors. Annu Rev Nutr. 1996, 16: 501-521. 10.1146/annurev.nu.16.070196.002441.PubMedCrossRef
3.
Weitman SD, Weinberg AG, Coney LR, Zurawski VR, Jennings DS, Kamen BA: Cellular localization of the folate receptor: potential role in drug toxicity and folate homeostasis. Cancer Res. 1992, 52 (23): 6708-6711.PubMed
4.
Kamen BA, Smith AK: A review of folate receptor alpha cycling and 5-methyltetrahydrofolate accumulation with an emphasis on cell models in vitro. Adv Drug Deliv Rev. 2004, 56 (8): 1085-1097. 10.1016/j.addr.2004.01.002.PubMedCrossRef
5.
Xia W, Hilgenbrink AR, Matteson EL, Lockwood MB, Cheng JX, Low PS: A functional folate receptor is induced during macrophage activation and can be used to target drugs to activated macrophages. Blood. 2009, 113 (2): 438-446.PubMedCrossRef
6.
Shen F, Wu M, Ross JF, Miller D, Ratnam M: Folate receptor type gamma is primarily a secretory protein due to lack of an efficient signal for glycosylphosphatidylinositol modification: protein characterization and cell type specificity. Biochemistry. 1995, 34 (16): 5660-5665. 10.1021/bi00016a042.PubMedCrossRef
7.
Blom HJ: Folic acid, methylation and neural tube closure in humans. Birth Defects Res A Clin Mol Teratol. 2009, 85 (4): 295-302. 10.1002/bdra.20581.PubMedCrossRef
8.
Spiegelstein O, Eudy JD, Finnell RH: Identification of two putative novel folate receptor genes in humans and mouse. Gene. 2000, 258 (1–2): 117-125.PubMedCrossRef
9.
Low PS, Kularatne SA: Folate-targeted therapeutic and imaging agents for cancer. Curr Opin Chem Biol. 2009, 13 (3): 256-262. 10.1016/j.cbpa.2009.03.022.PubMedCrossRef
10.
Barber RC, Bennett GD, Greer KA, Finnell RH: Expression patterns of folate binding proteins one and two in the developing mouse embryo. Mol Genet Metab. 1999, 66 (1): 31-39. 10.1006/mgme.1998.2772.PubMedCrossRef
11.
Elnakat H, Ratnam M: Distribution, functionality and gene regulation of folate receptor isoforms: implications in targeted therapy. Adv Drug Deliv Rev. 2004, 56 (8): 1067-1084. 10.1016/j.addr.2004.01.001.PubMedCrossRef
12.
13.
Yamaguchi T, Hirota K, Nagahama K, Ohkawa K, Takahashi T, Nomura T, Sakaguchi S: Control of immune responses by antigen-specific regulatory T cells expressing the folate receptor. Immunity. 2007, 27 (1): 145-159. 10.1016/j.immuni.2007.04.017.PubMedCrossRef
14.
Jia Z, Zhao R, Tian Y, Huang Z, Tian Z, Shen Z, Wang Q, Wang J, Fu X, Wu Y: A novel splice variant of FR4 predominantly expressed in CD4 + CD25+ regulatory T cells. Immunol Invest. 2009, 38 (8): 718-729. 10.3109/08820130903171003.PubMedCrossRef
15.
Shimizu J, Yamazaki S, Takahashi T, Ishida Y, Sakaguchi S: Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol. 2002, 3 (2): 135-142. 10.1038/ni759.PubMedCrossRef
16.
Sega EI, Low PS: Tumor detection using folate receptor-targeted imaging agents. Cancer Metastasis Rev. 2008, 27 (4): 655-664. 10.1007/s10555-008-9155-6.PubMedCrossRef
17.
Fox-Walsh KL, Hertel KJ: Splice-site pairing is an intrinsically high fidelity process. Proc Natl Acad Sci USA. 2009, 106 (6): 1766-1771. 10.1073/pnas.0813128106.PubMedPubMedCentralCrossRef
18.
Pan Q, Shai O, Lee LJ, Frey BJ, Blencowe BJ: Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat Genet. 2008, 40 (12): 1413-1415. 10.1038/ng.259.PubMedCrossRef
19.
Hsu SN, Hertel KJ: Spliceosomes walk the line: splicing errors and their impact on cellular function. RNA Biol. 2009, 6 (5): 526-530. 10.4161/rna.6.5.9860.PubMedPubMedCentralCrossRef
20.
Sestili P, Barbieri E, Martinelli C, Battistelli M, Guescini M, Vallorani L, Casadei L, D'Emilio A, Falcieri E, Piccoli G: Creatine supplementation prevents the inhibition of myogenic differentiation in oxidatively injured C2C12 murine myoblasts. Mol Nutr Food Res. 2009, 53 (9): 1187-1204. 10.1002/mnfr.200800504.PubMedCrossRef
21.
Annibalini G, Guescini M, Agostini D, Matteis RD, Sestili P, Tibollo P, Mantuano M, Martinelli C, Stocchi V: The expression analysis of mouse interleukin-6 splice variants argued against their biological relevance. BMB Rep. 2012, 45 (1): 32-37. 10.5483/BMBRep.2012.45.1.32.PubMedCrossRef
22.
Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY: A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol. 2005, 6 (11): 1142-1151. 10.1038/ni1263.PubMedCrossRef
23.
Hori S, Nomura T, Sakaguchi S: Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003, 299 (5609): 1057-1061. 10.1126/science.1079490.PubMedCrossRef
24.
Hoffmann P, Eder R, Kunz-Schughart LA, Andreesen R, Edinger M: Large-scale in vitro expansion of polyclonal human CD4(+)CD25high regulatory T cells. Blood. 2004, 104 (3): 895-903. 10.1182/blood-2004-01-0086.PubMedCrossRef
25.
Fantini MC, Dominitzki S, Rizzo A, Neurath MF, Becker C: In vitro generation of CD4+ CD25+ regulatory cells from murine naive T cells. Nat Protoc. 2007, 2 (7): 1789-1794. 10.1038/nprot.2007.258.PubMedCrossRef
Metadata
Title
A novel splice variant of folate receptor 4 predominantly expressed in regulatory T cells
Authors
Yi Tian
Guoqiang Wu
Jun-Chao Xing
Jun Tang
Yi Zhang
Ze-Min Huang
Zheng-Cai Jia
Ren Zhao
Zhi-Qiang Tian
Shu-Feng Wang
Xiao-Ling Chen
Li Wang
Yu-Zhang Wu
Bing Ni
Publication date
01-12-2012
Publisher
BioMed Central
Published in
BMC Immunology / Issue 1/2012
Electronic ISSN: 1471-2172
DOI
https://doi.org/10.1186/1471-2172-13-30

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