Abstract:

Pathways in the B7:CD28 family of costimulatory molecules regulate T cell activation and tolerance. B7-dependent responses in Cd28(-/-)Ctla4(-/-) T cells together with reports of stimulatory and inhibitory functions for Programmed Death-1 Ligand 1 or 2 molecules (PD-L1 or PD-L2) have suggested additional receptors for these B7 family members. We show that B7-1 and PD-L1 interacted with affinity intermediate to that of B7-1:CD28 and B7-1:CTLA-4. The PD-L1:B7-1 interface overlapped with the B7-1:CTLA-4 and PD-L1:PD-1 (Programmed Death-1) interfaces. T cell activation and cytokine production were inhibited by the interaction of B7-1 with PD-L1. The responses of PD-1-deficient versus PD-1,B7-1 double-deficient T cells to PD-L1 and of CD28,CTLA-4 double-deficient versus CD28,CTLA-4,PD-L1 triple-deficient T cells to B7-1 demonstrated that PD-L1 and B7-1 interact specifically to inhibit T cell activation. Our findings point to a substantial bidirectional inhibitory interaction between B7-1 and PD-L1 and add an additional dimension to immunoregulatory functions of the B7:CD28 family.

Open in

PUBMED | DOI | PMC | Google Scholar | Wikipedia

Relations:

Content

Citations

(485)

References

(54)

Clinical trials

(2)

Chemicals

(6)

Genes

(2)

Organisms

(6)

Processes

(3)

Anatomy

(4)

Affiliates

(1)

PD-L1 interacts specifically with B7-1 to inhibit T cell proliferation

^{Department of Pathology, Harvard Medical School, Boston, MA 02115, USA}

^{Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA}

^{Department of Medical Oncology, Dana Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA}

^{Co-Senior Authors}

^{Corresponding author:}ude.dravrah.smh@eprahs_enelra, 617-432-6569, fax: 617-432-6570

Copyright notice

Publisher's Disclaimer

Summary

Pathways in the B7:CD28 family regulate T cell activation and tolerance. B7 dependent responses in CD28/CTLA-4^-/- T cells together with reports of stimulatory and inhibitory functions for PD-L1 and PD-L2 have suggested additional receptors for these B7 family members. We show that B7-1 and PD-L1 interact with an affinity intermediate to that of B7-1:CD28 and B7-1:CTLA-4. The PD-L1:B7-1 interface overlaps with the B7-1:CTLA-4 and PD-L1:PD-1 interfaces. We show that the interaction of B7-1 with PD-L1 inhibits T cell activation and cytokine production by comparing responses of T cells deficient in the well-described (CD28, CTLA4, and PD-1) and newly-characterized (B7-1 and PD-L1) receptors to either B7-1-Ig or PD-L1-Ig. The responses of PD-1^-/- vs. PD-1/B7-1^-/- T cells to PD-L1 and CD28/CTLA-4^-/- vs. CD28/CTLA-4/PD-L1^-/- T cells to B7-1 demonstrate that PD-L1 and B7-1 interact specifically to inhibit T cell activation. Our findings point to a significant bidirectional inhibitory interaction between B7-1 and PD-L1 and add an additional dimension to immunoregulatory functions of the B7:CD28 family.

Summary

Footnotes

The authors disclose no financial conflicts of interest.

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Footnotes

Collaboration tool especially designed for Life Science professionals.Drag-and-drop any entity to your messages.

Learn More