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CD152 Ligation by CD80 on T Cells Is Required for the Induction of Unresponsiveness by Costimulation-Deficient Antigen Presentation¹

Jian-Guo Chai^2,*, Silvia Vendetti^2,*, Eunice Amofah^*, Julian Dyson and Robert Lechler^3,*

^* Department of Immunology, Imperial College School of Medicine, and Transplantation Biology Group, Medical Research Council Clinical Sciences Centre, Hammersmith Hospital, London, United Kingdom

Two apparently contradictory observations have been made concerning peripheral T cell tolerance; costimulation-deficient Ag presentation leads to unresponsiveness, and CTLA4 (CD152) ligation is required for unresponsiveness to be induced. This issue was addressed using a CD80^- CD86^low B cell line to present Ag to DO.11.10 naive CD4⁺ T cells. Proliferation was substantially enhanced by anti-CD80 or anti-CD152, but was inhibited by anti-CD86. Furthermore, anti-CD80 partially, and anti-CD152 totally protected cloned DO.11.10 T cells from the induction of unresponsiveness following culture with peptide and Chinese hamster ovary H2-A^d+ CD80^- CD86^- cells. Fab of anti-CD80 caused similar enhancement, and coimmobilized anti-CD80 failed to costimulate the anti-CD3 response of purified T cells, indicating that direct signaling by anti-CD80 was not responsible for these effects. The possibility that anti-CD80 liberated CD28 molecules that were sequestered by the T cell-expressed CD80, enabling them to coaggregate with TCR:CD3 complexes was excluded by finding that anti-CD80 and anti-CD152 individually caused maximal enhancement, rather than having additive effects. These data suggest that T cell-expressed CD80 has a regulatory function and plays a key role in the induction of unresponsiveness due to costimulation-deficient Ag presentation by the ligation of CD152 on neighboring, or even the same, T cell.

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