Abstract
T-lymphocyte activation and immune function are regulated by co-stimulatory molecules. CD28, a receptor for B7 gene products, has a chief role in initiating T-cell immune responses1,2. CTLA4, which binds B7 with a higher affinity, is induced after T-cell activation and is involved in downregulating T-cell responses3,4. The inducible co-stimulatory molecule (ICOS), a third member of the CD28/CTLA4 family, is expressed on activated T cells5,6. Its ligand B7H/B7RP-1 is expressed on B cells and in non-immune tissues after injection of lipopolysaccharide into animals6,7. To understand the role of ICOS in T-cell activation and function, we generated and analysed ICOS-deficient mice. Here we show that T-cell activation and proliferation are defective in the absence of ICOS. In addition, ICOS-/- T cells fail to produce interleukin-4 when differentiated in vitro or when primed in vivo. ICOS is required for humoral immune responses after immunization with several antigens. ICOS-/- mice showed greatly enhanced susceptibility to experimental autoimmune encephalomyelitis, indicating that ICOS has a protective role in inflammatory autoimmune diseases.
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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).
Chambers, C. A. & Allison, J. P. Co-stimulatory regulation of T cell function. Curr. Opin. Cell Biol. 11, 203–210 (1999).
Thompson, C. B. & Allison, J. P. The emerging role of CTLA-4 as an immune attenuator. Immunity 7, 445–450 (1997).
Oosterwegel, M. A., Greenwald, R. J., Mandelbrot, D. A., Lorsbach, R. B. & Sharpe, A. H. CTLA-4 and T cell activation. Curr. Opin. Immunol. 11, 294–300 (1999).
Hutloff, A. et al. ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature 397, 263–266 (1999).
Yoshinaga, S. K. et al. T-cell co-stimulation through B7RP-1 and ICOS. Nature 402, 827–832 ( 1999).
Swallow, M. M., Wallin, J. J. & Sha, W. C. B7h, a novel co-stimulatory homolog of B7.1 and B7.2, is induced by TNFα. Immunity 11, 423 –432 (1999).
Kopf, M. et al. Inducible co-stimulator protein (ICOS) controls T helper cell subset polarization after virus and parasite infection. J. Exp. Med. 192, 53–62 (2000).
Coyle, A. J. et al. The CD28-related molecule ICOS is required for effective T cell–dependent immune responses. Immunity 13, 95–105 (2000).
Liu, Y. et al. Co-stimulation of murine CD4 T cell growth: cooperation between B7 and heat-stable antigen. Eur. J. Immunol. 22, 2855–2859 (1992); erratum ibid. 23, 780 (1993).
Juedes, A. E. et al. Kinetics and cellular origin of cytokines in the central nervous system: insight into mechanisms of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis. A critical role for lymphotoxin in experimental allergic encephalomyelitis. J. Immunol. 164, 419–426 (2000).
Suen, W. E., Bergman, C. M., Hjelmstrom, P. & Ruddle, N. H. A critical role for lymphotoxin in experimental allergic encephalomyelitis. J. Exp. Med. 186, 1233– 1240 (1997).
Oliveira-dos-Santos, A. J. et al. CD28 co-stimulation is crucial for the development of spontaneous autoimmune encephalomyelitis. J. Immunol. 162, 4490–4495 (1999).
Girvin, A. M. et al. A critical role for B7/CD28 co-stimulation in experimental autoimmune encephalomyelitis: a comparative study using co-stimulatory molecule-deficient mice and monoclonal antibody blockade. J. Immunol. 164, 136–143 (2000).
Chang, T. T., Jabs, C., Sobel, R. A., Kuchroo, V. K. & Sharpe, A. H. Studies in B7-deficient mice reveal a critical role for B7 co-stimulation in both induction and effector phases of experimental autoimmune encephalomyelitis. J. Exp. Med. 190, 733–740 (1999).
de Waal Malefyt, R. et al. Effects of IL-13 on phenotype, cytokine production, and cytotoxic function of human monocytes. Comparison with IL-4 and modulation by IFN-γ or IL-10. J. Immunol. 151, 6370– 6381 (1993).
Viale, G. & Vercelli, D. Interleukin-13 regulates the phenotype and function of human monocytes. Int. Arch. Allergy Immunol. 107, 176–178 (1995).
Cosentino, G. et al. IL-13 down-regulates CD14 expression and TNF-α secretion in normal human monocytes. J. Immunol. 155, 3145–3151 (1995).
Kim, C. et al. Interleukin-13 effectively down-regulates the monocyte inflammatory potential during traumatic stress. Arch. Surg. 130, 1330–1336 (1995).
Cash, E. et al. Macrophage-inactivating IL-13 suppresses experimental autoimmune encephalomyelitis in rats. J. Immunol. 153, 4258–4267 (1994).
Dong, C. et al. JNK is required for effector T-cell function but not for T-cell activation. Nature 405, 91– 94 (2000).
Dong, C. et al. Defective T cell differentiation in the absence of Jnk1. Science 282, 2092–2095 ( 1998).
Kung, T. T. et al. Characterization of a murine model of allergic pulmonary inflammation. Int. Arch. Allergy Immunol. 105, 83– 90 (1994).
Temann, U. A., Geba, G. P., Rankin, J. A. & Flavell, R. A. Expression of interleukin 9 in the lungs of transgenic mice causes airway inflammation, mast cell hyperplasia, and bronchial hyperresponsiveness. J. Exp. Med. 188, 1307–1320 (1998).
Acknowledgements
The authors thank C. L. Stewart for providing reagents; L. Evangelisti, D. Butkus, C. Hughes, J. Stein and M. Chen for technical assistance; E. Enyon for discussion; and F. Manzo for secretarial work. This work was supported by grants from the NIH (to R.A.F.), the National Multiple Sclerosis Society (to N.H.R.), the Sandler Program for Asthma Research (to R.A.F.) and the Howard Hughes Medical Institute. C.D. is a recipient of an Arthritis Investigator award, and J.A. and R.A.F. are Investigators of the Howard Hughes Medical Institute.
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Dong, C., Juedes, A., Temann, UA. et al. ICOS co-stimulatory receptor is essential for T-cell activation and function . Nature 409, 97–101 (2001). https://doi.org/10.1038/35051100
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DOI: https://doi.org/10.1038/35051100
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