Soluble IL7Rα Potentiates IL-7 Bioactivity and Promotes Autoimmunity

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2013 Apr 24

PMID 23610432

Citations 71

Authors

Wangko Lundstrom

Steven Highfill

Scott T R Walsh

Stephanie Beq

Elizabeth Morse

Ingrid Kockum

Lars Alfredsson

Tomas Olsson

Jan Hillert

Crystal L Mackall

Affiliations

Soon will be listed here.

Abstract

Human soluble interleukin-7 receptor (sIL7R)α circulates in high molar excess compared with IL-7, but its biology remains unclear. We demonstrate that sIL7Rα has moderate affinity for IL-7 but does not bind thymic stromal lymphopoietin. Functionally, sIL7Rα competes with cell-associated IL-7 receptor to diminish excessive IL-7 consumption and, thus, enhances the bioactivity of IL-7 when the cytokine is limited, as it is presumed to be in vivo. IL-7 signaling in the presence of sIL7Rα also diminishes expression of CD95 and suppressor of cytokine signaling 1, both regulatory molecules. Murine models confirm diminished consumption of IL-7 in the presence of sIL7Rα and also demonstrate a potentiating effect of sIL7Rα on IL-7-mediated homeostatic expansion and experimental autoimmune encephalomyelitis exacerbation. In multiple sclerosis and several other autoimmune diseases, IL7R genotype influences susceptibility. We measured increased sIL7Rα levels, as well as increased IL-7 levels, in multiple sclerosis patients with the predisposing IL7R genotype, consistent with diminished IL-7 consumption in vivo. This work demonstrates that sIL7Rα potentiates IL-7 bioactivity and provides a basis to explain the increased risk of autoimmunity observed in individuals with genotype-induced elevations of sIL7Rα.

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References

Wickham Jr J, Walsh S . Crystallization and preliminary X-ray diffraction of human interleukin-7 bound to unglycosylated and glycosylated forms of its alpha-receptor. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2007; 63(Pt 10):865-9. PMC: 2339731. DOI: 10.1107/S1744309107042807. View

Lundstrom W, Fewkes N, Mackall C . IL-7 in human health and disease. Semin Immunol. 2012; 24(3):218-24. PMC: 3358500. DOI: 10.1016/j.smim.2012.02.005. View

Tan J, Dudl E, Leroy E, Murray R, Sprent J, Weinberg K . IL-7 is critical for homeostatic proliferation and survival of naive T cells. Proc Natl Acad Sci U S A. 2001; 98(15):8732-7. PMC: 37504. DOI: 10.1073/pnas.161126098. View

Crawley A, Faucher S, Angel J . Soluble IL-7R alpha (sCD127) inhibits IL-7 activity and is increased in HIV infection. J Immunol. 2010; 184(9):4679-87. DOI: 10.4049/jimmunol.0903758. View

Hafler D, Compston A, Sawcer S, Lander E, Daly M, De Jager P . Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med. 2007; 357(9):851-62. DOI: 10.1056/NEJMoa073493. View

Visscher P, Montgomery G . Genome-wide association studies and human disease: from trickle to flood. JAMA. 2009; 302(18):2028-9. DOI: 10.1001/jama.2009.1643. View

Bergamaschi C, Bear J, Rosati M, Beach R, Alicea C, Sowder R . Circulating IL-15 exists as heterodimeric complex with soluble IL-15Rα in human and mouse serum. Blood. 2012; 120(1):e1-8. PMC: 3390963. DOI: 10.1182/blood-2011-10-384362. View

Park L, Friend D, Schmierer A, Dower S, Namen A . Murine interleukin 7 (IL-7) receptor. Characterization on an IL-7-dependent cell line. J Exp Med. 1990; 171(4):1073-89. PMC: 2187830. DOI: 10.1084/jem.171.4.1073. View

Liu X, Leung S, Wang C, Tan Z, Wang J, Guo T . Crucial role of interleukin-7 in T helper type 17 survival and expansion in autoimmune disease. Nat Med. 2010; 16(2):191-7. DOI: 10.1038/nm.2077. View

10.

Hoe E, McKay F, Schibeci S, Gandhi K, Heard R, Stewart G . Functionally significant differences in expression of disease-associated IL-7 receptor alpha haplotypes in CD4 T cells and dendritic cells. J Immunol. 2010; 184(5):2512-7. DOI: 10.4049/jimmunol.0902900. View

11.

Hodge J, Srinivasula S, Hu Z, Read S, Porter B, Kim I . Decreases in IL-7 levels during antiretroviral treatment of HIV infection suggest a primary mechanism of receptor-mediated clearance. Blood. 2011; 118(12):3244-53. PMC: 3179394. DOI: 10.1182/blood-2010-12-323600. View

12.

Kimura M, Pobezinsky L, Guinter T, Thomas J, Adams A, Park J . IL-7 signaling must be intermittent, not continuous, during CD8⁺ T cell homeostasis to promote cell survival instead of cell death. Nat Immunol. 2012; 14(2):143-51. PMC: 3552087. DOI: 10.1038/ni.2494. View

13.

Manolio T . Genomewide association studies and assessment of the risk of disease. N Engl J Med. 2010; 363(2):166-76. DOI: 10.1056/NEJMra0905980. View

14.

Penaranda C, Kuswanto W, Hofmann J, Kenefeck R, Narendran P, Walker L . IL-7 receptor blockade reverses autoimmune diabetes by promoting inhibition of effector/memory T cells. Proc Natl Acad Sci U S A. 2012; 109(31):12668-73. PMC: 3411948. DOI: 10.1073/pnas.1203692109. View

15.

Tomita T, Kanai T, Nemoto Y, Fujii T, Nozaki K, Okamoto R . Colitogenic CD4+ effector-memory T cells actively recirculate in chronic colitic mice. Inflamm Bowel Dis. 2008; 14(12):1630-40. DOI: 10.1002/ibd.20636. View

16.

Fluur C, De Milito A, Fry T, Vivar N, Eidsmo L, Atlas A . Potential role for IL-7 in Fas-mediated T cell apoptosis during HIV infection. J Immunol. 2007; 178(8):5340-50. DOI: 10.4049/jimmunol.178.8.5340. View

17.

Uehira M, Matsuda H, Nakamura A, Nishimoto H . Immunologic abnormalities exhibited in IL-7 transgenic mice with dermatitis. J Invest Dermatol. 1998; 110(5):740-5. DOI: 10.1046/j.1523-1747.1998.00179.x. View

18.

Calzascia T, Pellegrini M, Lin A, Garza K, Elford A, Shahinian A . CD4 T cells, lymphopenia, and IL-7 in a multistep pathway to autoimmunity. Proc Natl Acad Sci U S A. 2008; 105(8):2999-3004. PMC: 2268574. DOI: 10.1073/pnas.0712135105. View

19.

Hindorff L, Sethupathy P, Junkins H, Ramos E, Mehta J, Collins F . Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci U S A. 2009; 106(23):9362-7. PMC: 2687147. DOI: 10.1073/pnas.0903103106. View

20.

Morton T, Myszka D, Chaiken I . Interpreting complex binding kinetics from optical biosensors: a comparison of analysis by linearization, the integrated rate equation, and numerical integration. Anal Biochem. 1995; 227(1):176-85. DOI: 10.1006/abio.1995.1268. View