Abstract
Parasites exert a selection pressure on their hosts and are accountable for driving diversity within gene families and immune gene polymorphisms in a host population. The overwhelming response of regulatory T cells during infectious challenges directs the host immune system to lose the ability to mount parasite specific T cell responses. The underlying idea of this study is that regulatory single nucleotide polymorphism (SNPs) can cause significant changes in gene expression in functional immune genes. We identified and investigated regulatory SNPs in the promoter region of the FOXP3 gene in a group of Gabonese individuals exposed to a variety of parasitic infections. We identified two novel and one promoter variants in 40 individual subjects. We further validated these promoter variants for their allelic gene expression using transient transfection assays. Two promoter variants, −794 (C/G) and the other variant −734/−540 (C/T) revealed a significant higher expression of the reporter gene at basal level in comparison to the major allele. The identification of SNPs that modify function in the promoter regions could provide a basis for studying parasite susceptibility in association studies.
Similar content being viewed by others
References
Bacchetta R, Gambineri E, Roncarolo MG (2007) Role of regulatory T cells and FOXP3 in human diseases. J Allergy Clin Immunol 120:227–235
Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265
Bassuny WM, Ihara K, Sasaki Y, Kuromaru R, Kohno H, Matsuura N, Hara T (2003) A functional polymorphism in the promoter/enhancer region of the FOXP3/Scurfin gene associated with type 1 diabetes. Immunogenetics 55:149–156
Belkaid Y (2007) Regulatory T cells and infection: a dangerous necessity. Nat Rev Immunol 7:875–888
Belkaid Y, Rouse BT (2005) Natural regulatory T cells in infectious disease. Nat Immunol 6:353–360
Belkaid Y, Blank RB, Suffia I (2006) Natural regulatory T cells and parasites: a common quest for host homeostasis. Immunol Rev 212:287–300
Coffer PJ, Burgering BMT (2004) Forkhead-box transcription factors and their role in the immune system. Nat Rev Immunol 4:889–899
Gao L, Li K, Li F, Li H, Liu L, Wang L, Zhang ZD, Gao TW, Liu YF (2010) Polymorphisms in the FOXP3 gene in Han Chinese psoriasis patients. J Dermatol Sci 57:51–56
Gavin MA, Torgerson TR, Houston E, deRoos P, Ho WY, Stray-Pedersen A, Ocheltree EL, Greenberg PD, Ochs HD, Rudensky AY (2006) Single-cell analysis of normal and FOXP3-mutant human T cells: FOXP3 expression without regulatory T cell development. Proc Natl Acad Sci USA 103:6659–6664
Hoogendoorn B, Coleman SL, Guy CA, Smith K, Bowen T, Buckland PR, O'Donovan MC (2003) Functional analysis of human promoter polymorphisms. Hum Mol Genet 12:2249–2254
Hori S (2010) c-Rel: a pioneer in directing regulatory T-cell lineage commitment? Eur J Immunol 40:664–667
Hromas R, Collins SJ, Hickstein D, Raskind W, Deaven LL, Ohara P, Hagen FS, Kaushansky K (1991) A retinoic acid-responsive human zinc finger gene, Mzf-1, preferentially expressed in myeloid cells. J Biol Chem 266:14183–14187
Juliger S, Bongartz M, Luty AJF, Kremsner PG, Kun JFJ (2003) Functional analysis of a promoter variant of the gene encoding the interferon-gamma receptor chain I. Immunogenetics 54:675–680
Kim HP, Leonard WJ (2007) CREB/ATF-dependent T cell receptor-induced FoxP3 gene expression: a role for DNA methylation. J Exp Med 204:1543–1551
Lan Y, Tang XS, Qin J, Wu J, Qin JM (2010) Association of transcription factor FOXP3 gene polymorphism with genetic susceptibility to systematic lupus erythematosus in Guangxi Zhuang population. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 27(4):433–436
Lin W, Haribhai D, Relland LM, Truong N, Carlson MR, Williams CB, Chatila TA (2007) Regulatory T cell development in the absence of functional Foxp3. Nat Immunol 8:359–368
Long MX, Park SG, Strickland I, Hayden MS, Ghosh S (2009) Nuclear factor-kappa B modulates regulatory T cell development by directly regulating expression of Foxp3 transcription factor. Immunity 31:921–931
Maizels RM (2009) Parasite immunomodulation and polymorphisms of the immune system. J Biol 8:62
Marson A, Kretschmer K, Frampton GM, Jacobsen ES, Polansky JK, Maclsaac KD, Levine SS, Fraenkel E, von Boehmer H, Young RA (2007) Foxp3 occupancy and regulation of key target genes during T-cell stimulation. Nature 445:931–935
Morris JF, Rauscher FJ, Davis B, Klemsz M, Xu DW, Tenen D, Hromas R (1995) The myeloid zinc-finger gene, Mzf-1, regulates the Cd34 promoter in-vitro. Blood 86:3640–3647
Ono M, Yaguchi H, Ohkura N, Kitabayashi I, Nagamura Y, Nomura T, Miyachi Y, Tsukada T, Sakaguchi S (2007) Foxp3 controls regulatory T-cell function by interacting with AML1/Runx1. Nature 446:685–689
Park O, Grishina I, Leung P, Gershwin M, Prindiville T (2005) Analysis of the Foxp3/Scurfin gene in Crohn’s disease. Ann NY Acad Sci 1051:218–228
Rozen S, Skaletsky H (2000) Primer3 on the WWW for general users and for biologist programmers. Meth Mol Biol 132:365–386
Sakaguchi S (2003) Regulatory T cells: mediating compromises between host and parasite. Nat Immunol 4:10–11
Sakaguchi S, Wing K, Miyara M (2007) Regulatory T cells—a brief history and perspective. Eur J Immunol 37:S116–S123
van Loosdregt J, Vercoulen Y, Guichelaar T, Gent YYJ, Beekman JM, van Beekum O, Brenkman AB, Hijnen DJ, Mutis T, Kalkhoven E, Prakken BJ, Coffer PJ (2010) Regulation of Treg functionality by acetylation-mediated Foxp3 protein stabilization. Blood 115:965–974
Walther M, Tongren JE, Andrews L, Korbel D, King E, Fletcher H, Andersen RF, Bejon P, Thompson F, Dunachie SJ, Edele F, de Souza JB, Sinden RE, Gilbert SC, Riley EM, Hill AVS (2005) Upregulation of TGF-beta, FOXP3, and CD4(+)CD25(+) regulatory T cells correlates with more rapid parasite growth in human malaria infection. Immunity 23:287–296
Workman CJ, Szymczak-Workman AL, Collison LW, Pillai MR, Vignali DAA (2009) The development and function of regulatory T cells. Cell Mol Life Sci 66:2603–2622
Zheng Y, Josefowicz SZ, Kas A, Chu TT, Gavin MA, Rudensky AY (2007) Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells. Nature 445:936–940
Acknowledgments
We thank A. Weierich, V. Galinat, and V. Grummes for technical assistance during the study period. The project received funding from a grant of the EU commission—TRANCHI (INCO-CT-2006-032436).
Author information
Authors and Affiliations
Corresponding author
Additional information
Susanne A Hanel and Velavan TP equally contributed to the work.
Rights and permissions
About this article
Cite this article
Hanel, S.A., TP, V., Kremsner, P.G. et al. Novel and functional regulatory SNPs in the promoter region of FOXP3 gene in a Gabonese population. Immunogenetics 63, 409–415 (2011). https://doi.org/10.1007/s00251-011-0524-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00251-011-0524-x