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ICOS co-stimulatory receptor is essential for T-cell activation and function

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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Figure 1: Generation of ICOS knockout mice.
Figure 2: Defective T-cell activation in vitro by ICOS-/- cells.
Figure 3: Defective cytokine production by ICOS-/- cells.
Figure 4: ICOS-deficient animals have normal infiltration of the lung with inflammatory cells but are defective in antibody responses after antigen challenges of the airway.
Figure 5: ICOS-deficient mice are severely susceptible to EAE.

References

  1. 1

    Lenschow, D. J., Walunas, T. L. & Bluestone, J. A. CD28/B7 system of T cell co-stimulation. Annu. Rev. Immunol. 14, 233–258 (1996).

    CAS  Article  Google Scholar 

  2. 2

    Chambers, C. A. & Allison, J. P. Co-stimulatory regulation of T cell function. Curr. Opin. Cell Biol. 11, 203–210 (1999).

    CAS  Article  Google Scholar 

  3. 3

    Thompson, C. B. & Allison, J. P. The emerging role of CTLA-4 as an immune attenuator. Immunity 7, 445–450 (1997).

    CAS  Article  Google Scholar 

  4. 4

    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).

    CAS  Article  Google Scholar 

  5. 5

    Hutloff, A. et al. ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature 397, 263–266 (1999).

    ADS  CAS  Article  Google Scholar 

  6. 6

    Yoshinaga, S. K. et al. T-cell co-stimulation through B7RP-1 and ICOS. Nature 402, 827–832 ( 1999).

    ADS  CAS  Article  Google Scholar 

  7. 7

    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).

    CAS  Article  Google Scholar 

  8. 8

    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).

    CAS  Article  Google Scholar 

  9. 9

    Coyle, A. J. et al. The CD28-related molecule ICOS is required for effective T cell–dependent immune responses. Immunity 13, 95–105 (2000).

    CAS  Article  Google Scholar 

  10. 10

    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).

    CAS  Article  Google Scholar 

  11. 11

    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).

    CAS  Article  Google Scholar 

  12. 12

    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).

    CAS  Article  Google Scholar 

  13. 13

    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).

    CAS  PubMed  Google Scholar 

  14. 14

    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).

    CAS  Article  Google Scholar 

  15. 15

    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).

    CAS  Article  Google Scholar 

  16. 16

    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).

    CAS  PubMed  Google Scholar 

  17. 17

    Viale, G. & Vercelli, D. Interleukin-13 regulates the phenotype and function of human monocytes. Int. Arch. Allergy Immunol. 107, 176–178 (1995).

    CAS  Article  Google Scholar 

  18. 18

    Cosentino, G. et al. IL-13 down-regulates CD14 expression and TNF-α secretion in normal human monocytes. J. Immunol. 155, 3145–3151 (1995).

    CAS  PubMed  Google Scholar 

  19. 19

    Kim, C. et al. Interleukin-13 effectively down-regulates the monocyte inflammatory potential during traumatic stress. Arch. Surg. 130, 1330–1336 (1995).

    CAS  Article  Google Scholar 

  20. 20

    Cash, E. et al. Macrophage-inactivating IL-13 suppresses experimental autoimmune encephalomyelitis in rats. J. Immunol. 153, 4258–4267 (1994).

    CAS  PubMed  Google Scholar 

  21. 21

    Dong, C. et al. JNK is required for effector T-cell function but not for T-cell activation. Nature 405, 91– 94 (2000).

    ADS  CAS  Article  Google Scholar 

  22. 22

    Dong, C. et al. Defective T cell differentiation in the absence of Jnk1. Science 282, 2092–2095 ( 1998).

    ADS  CAS  Article  Google Scholar 

  23. 23

    Kung, T. T. et al. Characterization of a murine model of allergic pulmonary inflammation. Int. Arch. Allergy Immunol. 105, 83– 90 (1994).

    CAS  Article  Google Scholar 

  24. 24

    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).

    CAS  Article  Google Scholar 

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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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Correspondence to Richard A. Flavell.

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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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