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Linking innate and acquired immunity: divergent role of CD46 cytoplasmic domains in T cell–induced inflammation

Nature Immunology volume 3, pages 659–666 (2002)Cite this article

Abstract

CD46 is a widely expressed transmembrane protein that was initially identified as binding and inactivating C3b and C4b complement products. We used mice that were transgenic for one of two human CD46 isoforms that differ in their cytoplasmic domains (termed CD46-1 and CD46-2) to analyze the effect of CD46 stimulation on the immune response. We show here that CD46 can regulate inflammatory responses, either by inhibiting (CD46-1) or increasing (CD46-2) the contact hypersensitivity reaction. We found that engagement of CD46-1 or CD46-2 differentially affected CD8+ T cell cytotoxicity, CD4+ T cell proliferation, interleukin 2 (IL-2) and IL-10 production as well as tyrosine phosphorylation of Vav in T lymphocytes. These results indicate that CD46 plays a role in regulating the T cell–induced inflammatory reaction and in fine-tuning the cellular immune response by bridging innate and acquired immunity.

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Figure 1: Divergent roles played by CD46 cytoplasmic domains in CHS reactions.
Figure 2: CD46-mediated increase in the inflammatory response does not require CD46 expression on MHC class II+ cells.
Figure 3: CD46-mediated modulation of inflammatory responses requires CD46 expression on T lymphocytes.
Figure 4: CD46 cytoplasmic domains differently affect antigen-specific CTL activity.
Figure 5: CD46 engagement modifies cytokine production by CD4+ T lymphocytes.
Figure 6: CD46 cytoplasmic domains differentially affect CD4+ T cell proliferation.
Figure 7: CD46 cytoplasmic domains differently affect T cell morphological changes and Vav tyrosine phosphorylation.

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Acknowledgements

We thank J. F. Nicolas and J. Kehren for their help during the initiation of this work; J. K. Rose and S. Niewiesk for providing the recombinant viruses VSV-H and VSV; M. B. Villiers for providing C3b; D. Mathis for the PDOI-5 plasmid vector; S. Deforges and V. Lotteau for their help with ELISA; D. Aubert for the microinjection of the transgenic construction; T. Defrance, and N. Davoust for helpful comments; and S. Souchon for expert technical assistance. Supported by institutional grants from INSERM, MRT and Région Rhône Alpes (to F. W.) and grant number 4450 from ARC (to B. H.).

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  1. INSERM U404, Immunité et Vaccination, CERVI, 21 avenue Tony Garnier, Lyon, 69365, Cedex 07, France

    Julien C. Marie, T. Fabian Wild & Branka Horvat

  2. INSERM U503, Immunobiologie Fondamentale et Clinique, CERVI, 21 avenue Tony Garnier, Lyon, 69365, Cedex 07, France

    Anne L. Astier, Pierre Rivailler & Chantal Rabourdin-Combe

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Supplementary information

Web Fig. 1.

CD46-1 and CD46-2 differently affect the effector phase of CHS. Groups of five mice, (a) CD46-1–transgenic, (b) CD46-2–transgenic and (c) CIID, were sensitized with DNFB or left unsensitized and injected 5 days later intraperitoneally with either inactivated VSV or inactivated VSV-H. Mice were challenged on the ear 6 h after injection and ear swelling was measured daily. Results are expressed as mean ± s.d. ear swelling. (JPG 46 kb)

Web Fig. 2.

Comparison of the intensity of Vav tyrosine phosphorylation in T lymphocytes after different types of stimulation. Film, revealed after immunoblotting (see Fig.7b), was scanned and analyzed with an Image Master program. The relative abundance of Vav tyrosine phosphorylation was calculated as the Vav–P-Tyr:Vav band:volume ratio. (a) Analysis of T lymphocytes obtained from CD46-1–transgenic mice. (b) Analysis of T lymphocytes obtained from CD46-2–transgenic mice. (PDF 28 kb)

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Marie, J., Astier, A., Rivailler, P. et al. Linking innate and acquired immunity: divergent role of CD46 cytoplasmic domains in T cell–induced inflammation. Nat Immunol 3, 659–666 (2002). https://doi.org/10.1038/ni810

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