Abstract
We investigated how the accessory molecule interactions encountered during T cell priming influence T cell–mediated destruction of insulin-producing β cells and lead to type 1 diabetes. T cell receptor (TCR)-transgenic CD4+ T cells were primed under controlled conditions in vitro before being adoptively transferred into transgenic recipients expressing membrane ovalbumin under the control of the rat insulin promoter (RIP-mOVA). During priming, antigen-presenting cell expression of B7-1 without intracellular adhesion molecule 1 (ICAM-1) led to the generation of effector cells that migrated to the pancreata of RIP-mOVA recipients but did not cause diabetes. In contrast, when T cells were primed with APCs expressing both B7-1 and ICAM-1, pronounced destruction of β cells and a rapid onset of diabetes were observed. Pathogenicity was associated with T cell production of the macrophage-attracting chemokines CCL3 and CCL4. Thus, interactions of lymphocyte function–associated antigen 1 with ICAM-1 during priming induce both qualitative and quantitative alterations in T effector function and induce potentially autodestructive responses.
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References
Lenschow, D. J., Walunas, T. L. & Bluestone, J. A. CD28/B7 system of T cell co-stimulation. Annu. Rev. Immunol. 14, 233–258 (1996).
Linsley, P. S. & Ledbetter, J. A. The role of the CD28 receptor during T cell responses to antigen. Annu. Rev. Immunol. 11, 191–212 (1993).
Allison, J. P. & Krummel, M. F. The Yin and Yang of T cell costimulation. Science 270, 932–933 (1995).
Schwartz, R. H. Costimulation of T lymphocytes: The role of CD28, CTLA-4, and B7/BB1 in Interleukin-2 Production and Immunotherapy. Cell 71, 1065–1068 (1992).
Hintzen, R. Q. et al. Engagement of CD27 with its ligand CD70 provides a second signal for T cell activation. J. Immunol. 154, 2612–2623 (1995).
Yashiro, Y. et al. A fundamental difference in the capacity to induce proliferation of naive T cells between CD28 and other co-stimulatory molecules. Eur. J. Immunol. 28, 926–935 (1998).
Zuckerman, L. A., Pullen, L. & Miller, J. Functional consequences of costimulation by ICAM-1 on IL-2 gene expression and T cell activation. J. Immunol. 160, 3259–3268 (1998).
Kuchroo, V. K. et al. B7-1 and B7-2 costimulatory molecules activate differentially the Th1/Th2 developmental pathways: Application to autoimmune disease therapy. Cell 80, 707–718 (1995).
Freeman, G. J. et al. B7-1 and B7-2 do not deliver identical costimulatory signals, since B7-2 but not B7-1 preferentially costimulates the initial production of IL-4. Immunity 2, 523–532 (1995).
Gause, W., Urban, J., Linsley, P. & Lu, P. Role of B7 signaling in the differentiation of naive CD4+ T cells to effector interleukin-4-producing T helper cells. Immunol. Res. 14, 176–178 (1995).
King, C. L., Stupi, R. J., Craighead, N., June, C. H. & Thyponitis, G. CD28 activation promotes Th2 subset differentiation by human CD4+ cells. Eur. J. Immunol. 25, 587–595 (1995).
Lenschow, D. J. et al. CD28/B7 regulation of Th1 and Th2 subsets in the development of autoimmune diabetes. Immunity 5, 285–293 (1996).
Ranger, A. M., Das, M. P., Kuchroo, V. K. & Glimcher, L. H. B7-2 (CD86) is essential for the development of IL-4-producing T cells. Int. Immunol. 8, 1549–1560 (1996).
Rulifson, I. C., Sperling, A. I., Fields, P. E., Fitch, F. W. & Bluestone, J. A. CD28 costimulation promotes the production of Th2 cytokines. J. Immunol. 158, 658–665 (1997).
Rodriguez-Palmero, M., Hara, T., Thumbs, A. & Hunig, T. Triggering of T cell proliferation through CD28 induces GATA-3 and promotes T helper type 2 differentiation in vitro and in vivo. Eur. J. Immunol. 29, 3914–3924 (1999).
Lenschow, D. J. et al. Differential effects of anti-B7-1 and anti-B7.2 monoclonal antibody treatment on the development of diabetes in the nonobese diabetic mouse. J. Exp. Med. 181, 1145–1155 (1995).
Salomon, B. & Bluestone, J. A. LFA-1 interaction with ICAM-1 and ICAM-2 regulates Th2 cytokine production. J. Immunol. 161, 5138–5142 (1998).
Luksch, C. R. et al. Intercellular adhesion molecule-1 inhibits interleukin-4 production by naïve T cells. Proc. Natl Acad. Sci. USA 96, 3023–3028 (1999).
Kurts, C. et al. Constitutive class I-restricted exogenous presentation of self antigens in vivo. J. Exp. Med. 184, 923–930 (1996).
Cai, Z. et al. Transfected Drosophila cells as a probe for defining the minimal requirements for stimulating unprimed CD8+ T cells. Proc. Natl Acad. Sci. USA 93, 14736–14741 (1996).
van Seventer, G. A., Shimizu, Y., Horgan, K. J. & Shaw, S. The LFA-1 ligand ICAM-1 provides an important costimulatory signal for T cell receptor-mediated activation of resting T cells. J. Immunol. 144, 4579–4586 (1990).
Dubey, C., Croft, M. & Swain, S. Costimulatory requirements of naive CD4+ T cells. ICAM-1 or B7-1 can costimulate naive CD4 T cell activation but both are required for optimum response. J. Immunol. 155, 45–57 (1995).
Damle, N. K., Klussman, K., Linsley, P. S. & Aruffo, A. Differential costimulatory effects of adhesion molecules B7, ICAM-1, LFA-3, and VCAM-1 on resting and antigen-primed CD4+ T lymphocytes. J. Immunol. 148, 1985–1992 (1992).
Bachmann, M. F. et al. Distinct roles for LFA-1 and CD28 during activation of naive T cells: adhesion versus costimulation. Immunity 7, 549–557 (1997).
Rabinovitch, A. An update on cytokines in the pathogenesis of insulin-dependent diabetes mellitus. Diabetes Metab. Rev. 14, 129–151 (1998).
Delovitch, T. L. & Singh, B. The nonobese diabetic mouse as a model of autoimmune diabetes: immune dysregulation gets the NOD. Immunity 7, 727–738 (1997). [Erratum in Immunity 8, 531 (1998).]
Falcone, M. & Sarvetnick, N. The effect of local production of cytokines in the pathogenesis of insulin-dependent diabetes mellitus. Clin. Immunol. 90, 2–9 (1999).
Lafaille, J. J. The role of helper T cell subsets in autoimmune diseases. Cytokine Growth Factor Rev. 9, 139–151 (1998).
Liblau, R. S., Singer, S. M. & McDevitt, H. O. Th1 and Th2 CD4+ T cells in the pathogenesis of organ-specific autoimmune diseases. Immunol. Today 16, 34–38 (1995).
DeVries, M. E., Ran, L. & Kelvin, D. J. On the edge: the physiological and pathophysiological role of chemokines during inflammatory and immunological responses. Semin. Immunol. 11, 95–104 (1999).
Schimmer, R. C. et al. Streptococcal cell wall-induced arthritis. Requirements for neutrophils, P-selectin, intercellular adhesion molecule-1, and macrophage-inflammatory protein-2. J. Immunol. 159, 4103–4108 (1997).
Schrier, D. J., Schimmer, R. C., Flory, C. M., Tung, D. K. & Ward, P. A. Role of chemokines and cytokines in a reactivation model of arthritis in rats induced by injection with streptococcal cell walls. J. Leukoc. Biol. 63, 359–363 (1998).
Plater-Zyberk, C., Hoogewerf, A. J., Proudfoot, A. E., Power, C. A. & Wells, T. N. Effect of a CC chemokine receptor antagonist on collagen induced arthritis in DBA/1 mice. Immunol. Lett. 57, 117–120 (1997).
Gong, J. H., Ratkay, L. G., Waterfield, J. D. & Clark-Lewis, I. An antagonist of monocyte chemoattractant protein 1 (MCP-1) inhibits arthritis in the MRL-lpr mouse model. J. Exp. Med. 186, 131–137 (1997).
Grewal, I. S. et al. Transgenic monocyte chemoattractant protein-1 (MCP-1) in pancreatic islets produces monocyte-rich insulitis without diabetes: abrogation by a second transgene expressing systemic MCP-1. J. Immunol. 159, 401–408 (1997).
Karpus, W. J. et al. An important role for the chemokine macrophage inflammatory protein-1 α in the pathogenesis of the T cell-mediated autoimmune disease, experimental autoimmune encephalomyelitis. J. Immunol. 155, 5003–5010 (1995).
Godiska, R., Chantry, D., Dietsch, G. N. & Gray, P. W. Chemokine expression in murine experimental allergic encephalomyelitis. J. Neuroimmunol. 58, 167–176 (1995).
Glabinski, A. R., Tuohy, V. K. & Ransohoff, R. M. Expression of chemokines RANTES, MIP-1α and GRO-α correlates with inflammation in acute experimental autoimmune encephalomyelitis. Neuroimmunomodulation 5, 166–171 (1998).
Bradley, L. M. et al. Islet-specific Th1, but not Th2, cells secrete multiple chemokines and promote rapid induction of autoimmune diabetes. J. Immunol. 162, 2511–2520 (1999).
Nelson, P. J. & Krensky, A. M. Chemokines, lymphocytes and viruses: what goes around, comes around. Curr. Opin. Immunol. 10, 265–270 (1998).
Zlotnik, A., Morales, J. & Hedrick, J. A. Recent advances in chemokines and chemokine receptors. Crit. Rev. Immunol. 19, 1–47 (1999).
Kuhlman, P., Moy, V. T., Lollo, B. A. & Brian, A. A. The accessory function of murine intercellular adhesion molecule-1 in T lymphocyte activation. Contributions of adhesion and co-activation. J. Immunol. 146, 1773–1782 (1991).
Brunmark, A. & O'Rourke, A. M. Augmentation of mature CD4+ T cell responses to isolated antigenic class II proteins by fibronectin and intercellular adhesion molecule-1. J. Immunol. 159, 1676–1685 (1997).
van Seventer, G. A., Semnani, R. T., Palmer, E. M., McRae, B. L. & van Seventer, J. M. Integrins and T helper cell activation. Transplant Proc. 30, 4270–4274 (1998).
Dustin, M. L. et al. TCR-mediated adhesion of T cell hybridomas to planar bilayers containing purified MHC class II/peptide complexes and receptor shedding during detachment. J. Immunol. 157, 2014–2021 (1996).
Suri, A. & Katz, J. D. Dissecting the role of CD4+ T cells in autoimmune diabetes through the use of TCR transgenic mice. Immunol. Rev. 169, 55–65 (1999).
Jun, H. S., Yoon, C. S., Zbytnuik, L., van Rooijen, N. & Yoon, J. W. The role of macrophages in T cell-mediated autoimmune diabetes in nonobese diabetic mice. J. Exp. Med. 189, 347–358 (1999).
Benoist, C. & Mathis, D. Cell death mediators in autoimmune diabetes–no shortage of suspects. Cell 89, 1–3 (1997).
Vyth-Dreese, F. A. et al. Localization in situ of costimulatory molecules and cytokines in B-cell non-Hodgkin's lymphoma. Immunology 94, 580–586 (1998).
Rothe, H., Hibino, T., Itoh, Y., Kolb, H. & Martin, S. Systemic production of interferon-γ inducing factor (IGIF) versus local IFN-γ expression involved in the development of Th1 insulitis in NOD mice. J. Autoimmun. 10, 251–256 (1997).
Sabzevari, H., Propp, S., Kono, D. H. & Theofilopoulos, A. N. G1 arrest and high expression of cyclin kinase and apoptosis inhibitors in accumulated activated/memory phenotype CD4+ cells of older lupus mice. Eur. J. Immunol. 27, 1901–1910 (1997)
Acknowledgements
We thank B. Marchand for typing the manuscript and D. Redondo for technical assistance. Supported by grants CA41993, CA25803 and AI39664 from the United States Public Health Service, a grant from the Juvenile Diabetes Foundation and a grant from R. W. Johnson Pharmaceutical Research Institute.
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Camacho, S., Heath, W., Carbone, F. et al. A key role for ICAM-1 in generating effector cells mediating inflammatory responses. Nat Immunol 2, 523–529 (2001). https://doi.org/10.1038/88720
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DOI: https://doi.org/10.1038/88720
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