Abstract

Interactions of B7H1 (PD-L1) on antigen presenting cells with its two ligands, PD-1 and B7.1, on T cells play a pivotal role in controlling T cell activation, proliferation, anergy, and apoptosis. However, the interactions between the two pathways remain unknown. Using a graft-versus-host disease (GVHD) model of C57BL/6 donor to MHC-mismatched BALB/c recipient, we report here that:1) Wild-type (WT) conventional alloreactive CD4+ T (Tcon) cells induces more severe acute GVHD in B7H1 deficient recipients due to lack of both B7H1/PD-1 and B7H1/B7.1 interaction, resulting in reduced Tcon proliferation and apoptosis and therefore increased expansion of Tcon cells. In contrast, PD-1 deficient Tcon cells induced less severe GVHD in B7H1 deficient recipients compared to WT recipients due to lack of B7H1/B7.1 interaction and reduced Tcon cell proliferation. 2) Specific blockade of the B7H1/B7.1 axis by use of an anti-B7H1 mAb exacerbate acute GVHD. This is because anti-B7H1 mAb reduces donor Tcon cell proliferation, IL-2 production, expression of PD-1, and activation-induced apoptosis, resulting in expansion of alloreactive Tcon cells. In contrast, in the absence of PD-1 on donor T cells, specific blockade of B7H1/B7.1 interaction ameliorates acute GVHD due to reduction of donor Tcon proliferation without impact on Tcon cell apoptosis. 3) B7H1 fused to an immunoglobulin Fc domain (B7H1-Ig), when produced in vivo by hydrodynamic injection of B7H1 plasmid, ameliorates GVHD by augmenting both proliferation and apoptosis of WT- alloreactive Tcon cells. Conversely, in the absence of PD-1 on donor T cells, B7H1-Ig treatment has no impact on apoptosis but augments donor T cell proliferation and worsens GVHD. These results indicate that interaction of B7.1 with B7H1 augments Tcon cell proliferation, IL-2 production, and expression of PD-1. Higher expression of PD-1 leads to increased donor Tcon cell apoptosis mediated by the B7H1/PD1 pathway therefore ameliorates GVHD. But in the absence of PD-1, B7H1/B7.1 interaction only augments T cell proliferation and causes more severe GVHD. Additionally, by engaging both PD-1 and B7.1, B7H1-Ig can be a powerful therapeutic reagent for down-regulating the T cell immune response (This work was supported by NIH R01 AI066008).

Disclosures

No relevant conflicts of interest to declare.

Author notes

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Asterisk with author names denotes non-ASH members.