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The inhibitory function of B7 costimulators in T cell responses to foreign and self-antigens

Nature Immunology volume 4, pages 664–669 (2003)Cite this article

Abstract

When antigen-presenting cells (APCs) encounter inflammatory stimuli, they up-regulate their expression of B7. A small amount of B7 is also constitutively expressed on resting APCs, but its function is unclear. Here we show that initiation of T cell responses requires the expression of B7 on immunizing APCs, but the responses are much greater in the absence of basal B7 expression. Transfer of antigen-specific CD4+CD25+ cells reverses the increased responsiveness, and tolerance to a self-protein is broken by immunization in the absence of basal B7, thereby inducing autoimmunity. Similar loss of self-tolerance is seen on depletion of CD25+ cells. Thus, constitutively expressed B7 costimulators function to suppress T cell activation and maintain self-tolerance, principally by sustaining a population of regulatory T cells.

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Figure 1: Endogenous host B7-1 and B7-2 does not enhance T cell responses to peptide-pulsed DCs.
Figure 2: Immunization with antigen-pulsed wild-type DCs enhances the production of effector cyokines in B7KO compared to wild-type (WT) hosts.
Figure 3: Immunization of RIP-mOVA mice with OVA-pulsed DCs causes diabetes in B7KO mice.
Figure 4: CTLA-4 blockade enhances the production of effector cytokines in DC-immunized WT and B7KO hosts.
Figure 5: Antigen-specific CD4+CD25+ regulatory T cells reduce the effector cytokine response in B7KO hosts immunized with wild-type DCs.
Figure 6: Depletion of CD25+ cells causes diabetes in RIP-mOVA mice immunized with OVA-pulsed DCs.

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Acknowledgements

We thank C. McArthur for cell sorting; E. Kahn and A. Chodos for technical assistance; C. Benitez for mouse typing; Q. Tang and J. Bluestone for anti-CD25; D. Ginzinger for support with real-time PCR; and members of the Abbas laboratory and J. Bluestone for discussions and review of the manuscript. This work was supported by grants from the US National Institutes of Health (to A.K.A.) and from the Deutsche Forschungsgemeinschaft (to J.L. and B.K.)

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Author notes

  1. Jens Lohr and Birgit Knoechel: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, University of California San Francisco School of Medicine, San Francisco, 94143-0511, California, USA

    Jens Lohr, Birgit Knoechel, Shuwei Jiang & Abul K Abbas

  2. Department of Pathology, Brigham & Women's Hospital and Harvard Medical School, Boston, 02115, Massachusetts, USA

    Arlene H Sharpe

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Correspondence to Abul K Abbas.

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Supplementary information

Supplementary Fig. 1.

Adoptively transferred DO11 T cell are not reduced in spleens of RIP-mOVA mice compared to BALB/c. 5x106 CFSE-labeled DO11 CD4+ T cells were adoptively transferred into irradiated (500cGy) wild-type BALB/c or RIP-mOVA recipients on day 0. Spleens were harvested on d1, d2 and d3, and stained with anti-CD4 and KJ1-26. (a) FACS profile of lymphocytes recovered from spleens of wild-type and RIP-mOVA mice on day 1. The plot on the right is gated on CFSE-labeled CD4+ cells only. (b) Recovered CD4+ KJ1-26+ T cells from spleens of wild-type (open squares) and RIP-mOVA mice (filled diamonds) on day 1, 2 and 3 after adoptive transfer. Indicated numbers show the mean percentage of recovered KJ1-26+ CD4+ cells of transferred CFSE-labeled CD4+ cells from two individual mice. (PDF 223 kb)

Supplementary Fig. 2.

Activated antigen-specific CD4+CD25+ cells from sOVA Tg x DO11 mice mediate suppression in vitro. KJ1-26+CD4+CD25+ cells from sOVA Tg x DO11 mice were purified by cell sorting and activated for 4 days with anti-CD3/anti-CD28 and IL-2. 2.5x104 cells/well were cocultured with KJ1-26-CD4+CD25+ cells from DO11.10 mice (2.5x104/well) and 2.5x104/well mitomycin C treated BALB/c splenocytes and 1 µg/ml of OVA323–339 peptide for 60 h. [3H]thymidine (1 µCi/well) was added during the last 18 h of culture. (PDF 95 kb)

Supplementary Fig. 3.

Intravenous administration of anti-CD25 antibody leads to depletion of CD4+CD25+ cells in RIP-mOVA mice. Wild-type RIP-mOVA mice were injected intravenously with 500 μg of anti-CD25 antibody (Clone PC61). 3 days after injection animals were bled and PBMCs analyzed and compared to control mice. By staining with non-crossreactive anti-CD25 (7D4), depletion efficiency was >90% in all experiments. (PDF 160 kb)

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Lohr, J., Knoechel, B., Jiang, S. et al. The inhibitory function of B7 costimulators in T cell responses to foreign and self-antigens. Nat Immunol 4, 664–669 (2003). https://doi.org/10.1038/ni939

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