- Open Access
T cell integrin overexpression as a model of murine autoimmunity
Biological Procedures Online volume 5, pages 211–221 (2003)
Integrin adhesion molecules have important adhesion and signaling functions. They also play a central role in the pathogenesis of many autoimmune diseases. Over the past few years we have described a T cell adoptive transfer model to investigate the role of T cell integrin adhesion molecules in the development of autoimmunity. This report summarizes the methods we used in establishing this murine model. By treating murine CD4+ T cells with DNA hypomethylating agents and by transfection we were able to test thein vitro effects of integrin overexpression on T cell autoreactive proliferation, cytotoxicity, adhesion and trafficking. Furthermore, we showed that the ability to inducein vivo autoimmunity may be unique to the integrin lymphocyte function associated antigen-1 (LFA-1).
Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm.Cell 1994;76:301–314.
Kilger G, Holzmann B. 1995. Molecular analysis of the physiological and pathophysiological role of α4-integrins.J Mol Med 1995; 73:347–354.
Coppolino MG, Dedhar S. Bi-directional signal transduction by integrin receptors.Int J Biochem Cell Biol 2000; 32:171–188.
Hynes R. Integrins: bidirectional, allosteric signaling machines.Cell 2002; 110:673–687.
Nojima Y, Rothstein DM, Sugita K, Schlossman SF, Morimoto C. Ligation of VLA-4 on T cells stimulates tyrosine phosphorylation of a 105-kD protein.J Exp Med 1992; 175:1045–1053.
van Seventer GA, Newman W, Shimizu Y, Nutman TB, Tanaka Y, Horgan KJ, Gopal TV, Ennis E, O’Sullivan D, Grey H,et al. Analysis of T cell stimulation by superantigen plus major histocompatibility complex class II molecules or by CD3 monoclonal antibody: costimulation by purified adhesion ligands VCAM-1, ICAM-1, but not ELAM-1.J Exp Med 1991; 174:901–913.
van Seventer GA., Shimizu Y, Horgan KJ, Luce GE, Webb D, Shaw S. Remote T cell co-stimulation via LFA-1/ICAM-1 and CD2/LFA-3: demonstration with immobilized ligand/mAb and implication in monocyte-mediated costimulation.Eur J Immunol 1991; 21:1711–1718.
Damle NK, Klussman K, Leytze G, Aruffo A, Linsley PS, Ledbetter JA. Costimulation with integrin ligands intercellular adhesion molecule-1 or vascular cell adhesion molecule-1 augments activation-induced death of antigen-specific CD4+ T lymphocytes.J Immunol 1993; 151:2368–2379.
Richardson BC, Strahler JR, Pivirotto TS, Quddus J, Bayliss GE, Gross LA, O’Rourke KS, Powers D, Hanash SM, Johnson MA. Phenotypic and functional similarities between 5-azacytidine-treated T cells and a T cell subset in patients with active systemic lupus erythematosus.Arthritis Rheum 1992; 35:647–662.
Takeuchi T, Amano K, Sekine H, Koide J, Abe T. Upregulated expression and function of integrin adhesive receptors in systemic lupus erythematosus patients with vasculitis.J Clin Invest 1993; 92:3008–3016.
Karpova GV, Fomina TI, Abramova EV, Bel’skaya NV, Trofimova ES, Perel’muter VM. Hemopoietic and lymphoid organs in AKR/JY mice with thymic lymphoma.Bull Exp Biol Med 2002; 134(1):69–72.
Saizawa MK, Hug E, Haque S, Portoles P, Suzuki S, Eichmann K. Autoreactivity of low but not of high CD4 variants of an antigen-specific, I-A-restricted mouse T cell clone.J Immunol 1992; 148:702–709.
Murphy HS, Bakotoulos N, Dame MK, Varani J, Ward PA. Heterogeneity of vascular endothelial cell: Differences in susceptibility to neutrophil mediated injury.Microvasc Res 1998; 56:203–211.
Yung RL, Richardson BC. Role of T cell DNA methylation in lupus.Lupus 1994; 3:487–491.
Richardson BC, Yung RL. The role of DNA methylation in the regulation of cell function.J Lab Clin Med 1999; 134:333–340.
Attwood J, Yung RL, Richardson BC. DNA methylation and the regulation of gene expression.Cell Mol Life Sci 2002;59:241–257.
Richardson BC, Liebling MR, Hudson JL. CD4+ cells treated with DNA methylation inhibitors induce autologous B cell differentiation.Clin Immunol Immunopathol 1990;55:368–381.
Richardson BC, Powers D, Hooper F, Yung RL, O’Rourke K. Lymphocyte Function Associated Antigen-1 Overexpression and T Cell Autoreactivity.Arthritis Rheum 1994; 37:1363–1372.
Richardson B. Effect of an inhibitor of DNA methylation on T cells. II. 5-azacytidine induces self-reactivity in antigen-specific T4+ cells.Hum Immunol 1986; 17:456–470.
Cornacchia E, Golbus J, Maybaum J, Strahler J, Hanash S, Richardson B. Hydralazine and procainamide inhibit T cell DNA methylation and induce autereactivity.J Immunol 1988;140:2197–2200.
Gleichmann E, Van Elven EH, Van der Veen JP. A systemic lupus erythematosus (SLE)-like disease in mice induced by abnormal T-B cell cooperation. Preferential formation of autoantibodies characteristic of SLE.Eur J Immunol 1982; 12(2):152–159.
Pals ST, Radaszkiewicz T, Roozendaal L, Gleichmann E. Chronic progressive polyarthritis and other symptoms of collagen vascular disease induced by graft-vs-host reaction.J Immunol 1985; 134(3):1475–1482.
Gerszten RE, Luscinskas FW, Ding HT, Dichek DA, Stoolman LM, Gimbrone MA, Jr. Rosenzweig A. Adhesion of memory lymphocytes to vascular cell adhesion molecule-1-transduced human vascular endothelial cells under simulated physiological flow conditionsin vitro.Circ Res 1996;79:1205–1215.
Spertini O, Luscinskas FW, Kansas GS, Munro JM, Griffin JD, Gimbrone MA, Jr. and Tedder TF. Leukocyte adhesion molecule-1 (LAM-1, L-selectin) interacts with an inducible endothelial cell ligand to support leukocyte adhesion.J Immunol 1991; 147:2565–2573.
Yung RL, Powers D, Johnson K, Amento E, Carr D, Laing of drug-induced lupus. II. T Cells overexpressing LFA-1 cause a lupus-like disease in syngeneic mice.Journal of Clinical Investigation 1996; 97:2866–2871.
Mo RR, Eisenbraun JK, Sonstein J, Craig RA, Curtis JL, Stoolman LM, Yung RL. CD49d overexpression and T cell autoimmunity.J Immunol 2003; 171:745–753.
Quddus J, Johnson KJ, Gavalchin J, Amento EP, Warren JS, Chrisp C, Yung RL, Richardson BC. Treating activated CD4+ T cells with either of two distinct DNA methyltransferase inhibitors, 5-azacytidine or procainamide, is sufficient to induce a lupus-like disease in syngeneic mice.J Clin Invest 1993; 92:38–53.
Yung R, Kaplan M, Ray D, Schneider K, Mo RR, Johnson K, Richardson B. Autoreactive murine Th1 and Th2 cells kill syngeneic macrophages and induce autoantibodies.Lupus 2001; 10:539–546.
Yung RL, Quddus J, Chrisp CE, Johnson KJ, Richardson BC. Mechanisms of drug-induced lupus. I. Cloned Th2 cells modified with DNA methylation inhibitorsin vitro cause autoimmunityin vivo.J Immunol 1995; 154:3025–3035.
Yung R, Williams R, Johnson K, Stoolman L, Chang S, Richardson B. Mechanisms of drug-induced lupus III. Gender specific differences in splenic T cell homing explain increased disease severity in female mice.Arthritis Rheum 1997; 40:1334–1343.
Yung R, Chang S, Hemati N, Johnson K, Richardson B. Mechanisms of drug-induced lupus IV. Comparison of procainamide and hydralazine with analogs in vitro and in vivo.Arthritis Rheum 1997; 40:1436–1443.
Kaplan MJ, Ray D, Mo RR, Yung RL, Richardson BC. TRAIL (APO2 ligand) and TWEAK (Apo3 ligand) mediate CD4+ T cell killing of antigen-presenting macrophages.J Immunol 2000; 164:2897–2904.
Matsumoto G, Omi Y, Lee U, Nishimura T, Shindo J, Penninger JM. Adhesion mediated by LFA-1 is required for efficient IL-12-induced NK and NKT cell cytotoxicity.Eur J Immunol 2000; 30:3723–3731.
Poggi A, Carosio R, Spaggiari GM, Fortis C, Tambussi G, Dell’Antonio G, Dal Cin E, Rubartelli A, Zocchi MR. NK cell activation by dendritic cells is dependent on LFA-1- mediated induction of calcium-calmodulin kinase II: inhibition by HIV-1 Tat C-terminal domain.J Immunol 2002;168:95–101.
Wang P, Malkovsky M. Different roles of the CD2 and LFA-1 T-cell co-receptors for regulating cytotoxic, proliferative, and cytokine responses of human V gamma 9/V delta 2 T cells.Mol Med 2000; 6:196–207.
Huang GT, Zhang X, Park NH. Increased ICAM-1 expression in transformed human oral epithelial cells: molecular mechanism and functional role in peripheral blood mononuclear cell adhesion and lymphokine-activatedkiller cell cytotoxicity.Int J Oncol 2000; 17:479–486.
Kaplan MJ, Beretta-Hanash L, Yung R, Richardson BC. LFA-1 overexpression causes autoreactivity by overstabilizing low affinity TCR-Ia interactions.Immunol Invest 2000; 29:427–442.
Murphy HS, Sun Q, Murphy BA, Mo RR, Huo J, Chen J, Adams M, Chensue, SW, Richardson BC, Yung RL. Tissue Specific Effect of Estradiol on Endothelial Cell-Dependent Lymphocyte Recruitment (submitted).
Yung RL, Richardson BC. Drug-induced Rheumatic Syndromes.Bull Rheum Dis 2002; 51(4):1–5.
Published: October 24, 2003
About this article
Cite this article
Yung, R.L., Ray, D., Mo, R.R. et al. T cell integrin overexpression as a model of murine autoimmunity. Biol. Proced. Online 5, 211–221 (2003). https://doi.org/10.1251/bpo64
- DNA methylation