Murine B Cell Response to TLR7 Ligands Depends on an IFN-beta Feedback Loop

Overview

Journal J Immunol

Specialty Allergy & Immunology

Date 2009 Jul 10

PMID 19587008

Citations 74

Authors

Nathaniel M Green

Amy Laws

Kerstin Kiefer

Liliana Busconi

You-Me Kim

Melanie M Brinkmann

Erin Hodges Trail

Kei Yasuda

Sean R Christensen

Mark J Shlomchik

Stefanie Vogel

John H Connor

Hidde Ploegh

Dan Eilat

Ian R Rifkin

Jean Maguire van Seventer

Ann Marshak-Rothstein

Affiliations

Soon will be listed here.

Abstract

Type I IFNs play an important, yet poorly characterized, role in systemic lupus erythematosus. To better understand the interplay between type I IFNs and the activation of autoreactive B cells, we evaluated the effect of type I IFN receptor (IFNAR) deficiency in murine B cell responses to common TLR ligands. In comparison to wild-type B cells, TLR7-stimulated IFNAR(-/-) B cells proliferated significantly less well and did not up-regulate costimulatory molecules. By contrast, IFNAR1(-/-) B cells did not produce cytokines, but did proliferate and up-regulate activation markers in response to other TLR ligands. These defects were not due to a difference in the distribution of B cell populations or a failure to produce a soluble factor other than a type I IFN. Instead, the compromised response pattern reflected the disruption of an IFN-beta feedback loop and constitutively low expression of TLR7 in the IFNAR1(-/-) B cells. These results highlight subtle differences in the IFN dependence of TLR7 responses compared with other TLR-mediated B cell responses.

Citing Articles

IRF7 controls spontaneous autoimmune germinal center and plasma cell checkpoints.

Fike A, Bricker K, Gonzalez M, Maharjan A, Bui T, Nuon K bioRxiv. 2025; .

PMID: 39974943 PMC: 11838595. DOI: 10.1101/2025.02.04.636277.

Tyrosine kinase 2 modulates splenic B cells through type I IFN and TLR7 signaling.

Bodega-Mayor I, Delgado-Wicke P, Arrabal A, Alegria-Carrasco E, Nicolao-Gomez A, Jaen-Castano M Cell Mol Life Sci. 2024; 81(1):199.

PMID: 38683377 PMC: 11058799. DOI: 10.1007/s00018-024-05234-y.

Protective versus Pathogenic Type I Interferon Responses during Virus Infections.

Jung K, McKenna S, Vijayamahantesh V, He Y, Hahm B Viruses. 2023; 15(9).

PMID: 37766322 PMC: 10538102. DOI: 10.3390/v15091916.

Genetics of SLE: mechanistic insights from monogenic disease and disease-associated variants.

Vinuesa C, Shen N, Ware T Nat Rev Nephrol. 2023; 19(9):558-572.

PMID: 37438615 DOI: 10.1038/s41581-023-00732-x.

Leishmania donovani Exploits Tunneling Nanotubes for Dissemination and Propagation of B Cell Activation.

Stogerer T, Silva-Barrios S, Carmona-Perez L, Swaminathan S, Mai L, Leroux L Microbiol Spectr. 2023; 11(4):e0509622.

PMID: 37404188 PMC: 10434010. DOI: 10.1128/spectrum.05096-22.

References

Means T, Latz E, Hayashi F, Murali M, Golenbock D, Luster A . Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9. J Clin Invest. 2005; 115(2):407-17. PMC: 544604. DOI: 10.1172/JCI23025. View

Santiago-Raber M, Baccala R, Haraldsson K, Choubey D, Stewart T, Kono D . Type-I interferon receptor deficiency reduces lupus-like disease in NZB mice. J Exp Med. 2003; 197(6):777-88. PMC: 2193854. DOI: 10.1084/jem.20021996. View

Banchereau J, Pascual V . Type I interferon in systemic lupus erythematosus and other autoimmune diseases. Immunity. 2006; 25(3):383-92. DOI: 10.1016/j.immuni.2006.08.010. View

Hron J, Peng S . Type I IFN protects against murine lupus. J Immunol. 2004; 173(3):2134-42. DOI: 10.4049/jimmunol.173.3.2134. View

Pogue S, Preston B, Stalder J, Bebbington C, Cardarelli P . The receptor for type I IFNs is highly expressed on peripheral blood B cells and monocytes and mediates a distinct profile of differentiation and activation of these cells. J Interferon Cytokine Res. 2004; 24(2):131-9. DOI: 10.1089/107999004322813372. View

Deonarain R, Verma A, Porter A, Gewert D, Platanias L, Fish E . Critical roles for IFN-beta in lymphoid development, myelopoiesis, and tumor development: links to tumor necrosis factor alpha. Proc Natl Acad Sci U S A. 2003; 100(23):13453-8. PMC: 263835. DOI: 10.1073/pnas.2230460100. View

Krumbholz M, Faber H, Steinmeyer F, Hoffmann L, Kumpfel T, Pellkofer H . Interferon-beta increases BAFF levels in multiple sclerosis: implications for B cell autoimmunity. Brain. 2008; 131(Pt 6):1455-63. DOI: 10.1093/brain/awn077. View

Braun D, Caramalho I, Demengeot J . IFN-alpha/beta enhances BCR-dependent B cell responses. Int Immunol. 2002; 14(4):411-9. DOI: 10.1093/intimm/14.4.411. View

Hua J, Kirou K, Lee C, Crow M . Functional assay of type I interferon in systemic lupus erythematosus plasma and association with anti-RNA binding protein autoantibodies. Arthritis Rheum. 2006; 54(6):1906-16. DOI: 10.1002/art.21890. View

10.

Brinkmann M, Spooner E, Hoebe K, Beutler B, Ploegh H, Kim Y . The interaction between the ER membrane protein UNC93B and TLR3, 7, and 9 is crucial for TLR signaling. J Cell Biol. 2007; 177(2):265-75. PMC: 2064135. DOI: 10.1083/jcb.200612056. View

11.

Symons J, Alcami A, Smith G . Vaccinia virus encodes a soluble type I interferon receptor of novel structure and broad species specificity. Cell. 1995; 81(4):551-60. DOI: 10.1016/0092-8674(95)90076-4. View

12.

Bennett L, Palucka A, Arce E, Cantrell V, Borvak J, Banchereau J . Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J Exp Med. 2003; 197(6):711-23. PMC: 2193846. DOI: 10.1084/jem.20021553. View

13.

Savarese E, Chae O, Trowitzsch S, Weber G, Kastner B, Akira S . U1 small nuclear ribonucleoprotein immune complexes induce type I interferon in plasmacytoid dendritic cells through TLR7. Blood. 2005; 107(8):3229-34. DOI: 10.1182/blood-2005-07-2650. View

14.

Honda K, Taniguchi T . IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors. Nat Rev Immunol. 2006; 6(9):644-58. DOI: 10.1038/nri1900. View

15.

Fenner J, Starr R, Cornish A, Zhang J, Metcalf D, Schreiber R . Suppressor of cytokine signaling 1 regulates the immune response to infection by a unique inhibition of type I interferon activity. Nat Immunol. 2005; 7(1):33-9. DOI: 10.1038/ni1287. View

16.

Lenert P, Brummel R, Field E, Ashman R . TLR-9 activation of marginal zone B cells in lupus mice regulates immunity through increased IL-10 production. J Clin Immunol. 2005; 25(1):29-40. DOI: 10.1007/s10875-005-0355-6. View

17.

Ronnblom L, Alm G . An etiopathogenic role for the type I IFN system in SLE. Trends Immunol. 2001; 22(8):427-31. DOI: 10.1016/s1471-4906(01)01955-x. View

18.

Fiette L, Aubert C, Muller U, Huang S, Aguet M, Brahic M . Theiler's virus infection of 129Sv mice that lack the interferon alpha/beta or interferon gamma receptors. J Exp Med. 1995; 181(6):2069-76. PMC: 2192065. DOI: 10.1084/jem.181.6.2069. View

19.

Bekeredjian-Ding I, Berkeredjian-Ding I, Wagner M, Hornung V, Giese T, Schnurr M . Plasmacytoid dendritic cells control TLR7 sensitivity of naive B cells via type I IFN. J Immunol. 2005; 174(7):4043-50. DOI: 10.4049/jimmunol.174.7.4043. View

20.

Braun D, Geraldes P, Demengeot J . Type I Interferon controls the onset and severity of autoimmune manifestations in lpr mice. J Autoimmun. 2003; 20(1):15-25. DOI: 10.1016/s0896-8411(02)00109-9. View