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

BMC Immunology

Bing Ni¹  Yu-Zhang Wu¹  Li Wang¹  Xiao-Ling Chen¹  Shu-Feng Wang¹  Zhi-Qiang Tian¹  Ren Zhao¹  Zheng-Cai Jia¹  Ze-Min Huang¹  Yi Zhang¹  Jun Tang³  Jun-Chao Xing²  Guoqiang Wu²  Yi Tian¹ 

[1] Institute of Immunology, PLA, Third Military Medical University, Chongqing 400038, Peoples Republic China;Department of general surgery, the general hospital of ShenYang military area command, ShenYang 110016, Peoples Republic of China;Department of Dermatology, the 105th Hospital of PLA, Hefei 230001, Peoples Republic of China

关键词: Proliferation;    Regulatory T cells;    Variant;    Folate receptor 4;   

Others  :  1077908
DOI  :  10.1186/1471-2172-13-30

 received in 2012-03-23, accepted in 2012-06-13,  发布年份 2012

【 摘 要 】

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.

【 授权许可】

   
2012 Tian et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】

• [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.
• [2]Antony AC: Folate receptors. Annu Rev Nutr 1996, 16:501-521.
• [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.
• [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.
• [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.
• [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.
• [7]Blom HJ: Folic acid, methylation and neural tube closure in humans. Birth Defects Res A Clin Mol Teratol 2009, 85(4):295-302.
• [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.
• [9]Low PS, Kularatne SA: Folate-targeted therapeutic and imaging agents for cancer. Curr Opin Chem Biol 2009, 13(3):256-262.
• [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.
• [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.
• [12]Vignali DA, Collison LW, Workman CJ: How regulatory T cells work. Nat Rev Immunol 2008, 8(7):523-532.
• [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.
• [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.
• [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.
• [16]Sega EI, Low PS: Tumor detection using folate receptor-targeted imaging agents. Cancer Metastasis Rev 2008, 27(4):655-664.
• [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.
• [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.
• [19]Hsu SN, Hertel KJ: Spliceosomes walk the line: splicing errors and their impact on cellular function. RNA Biol 2009, 6(5):526-530.
• [20]Sestili P, Barbieri E, Martinelli C, Battistelli M, Guescini M, Vallorani L, Casadei L, D'Emilio A, Falcieri E, Piccoli G, et al.: Creatine supplementation prevents the inhibition of myogenic differentiation in oxidatively injured C2C12 murine myoblasts. Mol Nutr Food Res 2009, 53(9):1187-1204.
• [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.
• [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.
• [23]Hori S, Nomura T, Sakaguchi S: Control of regulatory T cell development by the transcription factor Foxp3. Science 2003, 299(5609):1057-1061.
• [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.
• [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.