T Cells Stimulated with an Analog Peptide of Type II Collagen Require the Fc Receptor γ-chain to Secrete Interleukin-4 and Suppress Autoimmune Arthritis in Mice

Overview

Journal Arthritis Rheum

Specialty Rheumatology

Date 2011 May 19

PMID 21590683

Citations 4

Authors

Linda K Myers

David L Cullins

David D Brand

Sandra Kleinau

John M Stuart

Andrew H Kang

Affiliations

Soon will be listed here.

Abstract

Objective: To explore the characteristics of the T cell population that responds to an analog peptide (A9) of type II collagen and regulates autoimmunity, using the collagen-induced arthritis (CIA) model.

Methods: Analog peptide A9 is a 26-amino acid peptide analogous to the sequence of a segment of type II collagen (CII245-270) but with substitutions at amino acid positions 260 (alanine for isoleucine), 261 (hydroxyproline for alanine), and 263 (asparagine for phenylalanine). We previously showed that A9 profoundly suppressed CIA and immune responses to type II collagen. In order to determine the mechanism of suppression, we used transgenic mice whose T cells express a type II collagen-specific receptor (T cell receptor) and performed passive cell transfer experiments.

Results: The results demonstrated that suppression of CIA by A9 is dependent on T cells. Using multiparameter flow cytometry, we determined that the cells responsible for suppression were CD4+ and expressed high levels of Fcε receptor Iγ chain (FcRγ). To establish the significance of this finding, we obtained mice genetically deficient in FcRγ in order to perform passive transfer experiments. The resulting FcRγ-/- CD4+ T cells, when primed by culture with A9, could not transfer the suppression of arthritis or secrete cytokines in response to A9.

Conclusion: Taken together, the results of this study suggest that the suppression of arthritis and the Th2 cytokine profile elicited by A9 is dependent on the presence of FcRγ in T cells. These findings are novel and may have therapeutic potential for patients with autoimmune arthritis.

Citing Articles

Peptide-Based Vaccination Therapy for Rheumatic Diseases.

Wang B, Chen S, Zheng Q, Liu Y, Shi G J Immunol Res. 2020; 2020:8060375.

PMID: 32258176 PMC: 7104265. DOI: 10.1155/2020/8060375.

Peptide ligand structure and I-Aq binding avidity influence T cell signaling pathway utilization.

Myers L, Cullins D, Park J, Yi A, Brand D, Rosloniec E Clin Immunol. 2015; 160(2):188-97.

PMID: 25982319 PMC: 4959786. DOI: 10.1016/j.clim.2015.05.002.

Characterization of T cell phenotype and function in a double transgenic (collagen-specific TCR/HLA-DR1) humanized model of arthritis.

Tang B, Kim S, Hammond S, Cullins D, Brand D, Rosloniec E Arthritis Res Ther. 2014; 16(1):R7.

PMID: 24405551 PMC: 3978884. DOI: 10.1186/ar4433.

Characterization of inhibitory T cells induced by an analog of type II collagen in an HLA-DR1 humanized mouse model of autoimmune arthritis.

Kimata M, Cullins D, Brown M, Brand D, Rosloniec E, Myers L Arthritis Res Ther. 2012; 14(3):R107.

PMID: 22569209 PMC: 3446484. DOI: 10.1186/ar3832.

References

Bielekova B, Martin R . Antigen-specific immunomodulation via altered peptide ligands. J Mol Med (Berl). 2001; 79(10):552-65. DOI: 10.1007/s001090100259. View

Bielekova B, Goodwin B, Richert N, Cortese I, Kondo T, Afshar G . Encephalitogenic potential of the myelin basic protein peptide (amino acids 83-99) in multiple sclerosis: results of a phase II clinical trial with an altered peptide ligand. Nat Med. 2000; 6(10):1167-75. DOI: 10.1038/80516. View

Myers L, Rosloniec E, Seyer J, Stuart J, Kang A . A synthetic peptide analogue of a determinant of type II collagen prevents the onset of collagen-induced arthritis. J Immunol. 1993; 150(10):4652-8. View

Tang B, Zhou J, Park J, Cullins D, Yi A, Kang A . T cell receptor signaling induced by an analog peptide of type II collagen requires activation of Syk. Clin Immunol. 2009; 133(1):145-53. PMC: 2756788. DOI: 10.1016/j.clim.2009.06.006. View

Myers L, Tang B, Stuart J, Kang A . The role of IL-4 in regulation of murine collagen-induced arthritis. Clin Immunol. 2002; 102(2):185-91. DOI: 10.1006/clim.2001.5162. View

Myers L, Tang B, Rosioniec E, Stuart J, Kang A . An altered peptide ligand of type II collagen suppresses autoimmune arthritis. Crit Rev Immunol. 2008; 27(4):345-56. DOI: 10.1615/critrevimmunol.v27.i4.40. View

Kleinau S . The impact of Fc receptors on the development of autoimmune diseases. Curr Pharm Des. 2003; 9(23):1861-70. DOI: 10.2174/1381612033454414. View

Rosloniec E, Cremer M, Kang A, Myers L, Brand D . Collagen-induced arthritis. Curr Protoc Immunol. 2010; Chapter 15:15.5.1-15.5.25. DOI: 10.1002/0471142735.im1505s89. View

Nishibori T, Tanabe Y, Su L, David M . Impaired development of CD4+ CD25+ regulatory T cells in the absence of STAT1: increased susceptibility to autoimmune disease. J Exp Med. 2003; 199(1):25-34. PMC: 1193645. DOI: 10.1084/jem.20020509. View

10.

Chentouf M, Ghannam S, Bes C, Troadec S, Cerutti M, Chardes T . Recombinant anti-CD4 antibody 13B8.2 blocks membrane-proximal events by excluding the Zap70 molecule and downstream targets SLP-76, PLC gamma 1, and Vav-1 from the CD4-segregated Brij 98 detergent-resistant raft domains. J Immunol. 2007; 179(1):409-20. DOI: 10.4049/jimmunol.179.1.409. View

11.

Kappos L, Comi G, Panitch H, Oger J, Antel J, Conlon P . Induction of a non-encephalitogenic type 2 T helper-cell autoimmune response in multiple sclerosis after administration of an altered peptide ligand in a placebo-controlled, randomized phase II trial. The Altered Peptide Ligand in Relapsing MS Study.... Nat Med. 2000; 6(10):1176-82. DOI: 10.1038/80525. View

12.

Zhu J, Yamane H, Paul W . Differentiation of effector CD4 T cell populations (*). Annu Rev Immunol. 2010; 28:445-89. PMC: 3502616. DOI: 10.1146/annurev-immunol-030409-101212. View

13.

Godfrey D, Stankovic S, Baxter A . Raising the NKT cell family. Nat Immunol. 2010; 11(3):197-206. DOI: 10.1038/ni.1841. View

14.

Kleinau S, Martinsson P, Heyman B . Induction and suppression of collagen-induced arthritis is dependent on distinct fcgamma receptors. J Exp Med. 2000; 191(9):1611-6. PMC: 2213438. DOI: 10.1084/jem.191.9.1611. View

15.

Krishnan S, Juang Y, Chowdhury B, Magilavy A, Fisher C, Nguyen H . Differential expression and molecular associations of Syk in systemic lupus erythematosus T cells. J Immunol. 2008; 181(11):8145-52. PMC: 2586973. DOI: 10.4049/jimmunol.181.11.8145. View

16.

Brand D, Myers L, Whittington K, Latham K, Stuart J, Kang A . Detection of early changes in autoimmune T cell phenotype and function following intravenous administration of type II collagen in a TCR-transgenic model. J Immunol. 2001; 168(1):490-8. DOI: 10.4049/jimmunol.168.1.490. View

17.

Leipe J, Skapenko A, Lipsky P, Schulze-Koops H . Regulatory T cells in rheumatoid arthritis. Arthritis Res Ther. 2005; 7(3):93. PMC: 1174956. DOI: 10.1186/ar1718. View

18.

Koffeman E, Genovese M, Amox D, Keogh E, Santana E, Matteson E . Epitope-specific immunotherapy of rheumatoid arthritis: clinical responsiveness occurs with immune deviation and relies on the expression of a cluster of molecules associated with T cell tolerance in a double-blind, placebo-controlled, pilot phase.... Arthritis Rheum. 2009; 60(11):3207-16. DOI: 10.1002/art.24916. View

19.

Kim H, Antel J, Duquette P, Alleva D, Conlon P, Bar-Or A . Persistence of immune responses to altered and native myelin antigens in patients with multiple sclerosis treated with altered peptide ligand. Clin Immunol. 2002; 104(2):105-14. DOI: 10.1006/clim.2002.5258. View

20.

Prakken B, Samodal R, Le T, Giannoni F, Puga Yung G, Scavulli J . Epitope-specific immunotherapy induces immune deviation of proinflammatory T cells in rheumatoid arthritis. Proc Natl Acad Sci U S A. 2004; 101(12):4228-33. PMC: 384723. DOI: 10.1073/pnas.0400061101. View