PD-L1-Deficient Mice Show That PD-L1 on T Cells, Antigen-Presenting Cells, and Host Tissues Negatively Regulates T Cells

Both positive and negative regulatory roles have been suggested for the B7 family member PD-L1(B7-H1). PD-L1 is expressed on antigen-presenting cells (APCs), activated T cells, and a variety of tissues, but the functional significance of PD-L1 on each cell type is not yet clear. To dissect the functions of PD-L1 in vivo, we generated PD-L1-deficient ( PD- L1-/-) mice. CD4+and CD8+T cell responses were markedly enhanced in PD- L1-/-mice compared with wild-type mice in vitro and in vivo. PD- L1-/-dendritic cells stimulated greater wild-type CD4+T cell responses than wild-type dendritic cells, and PD- L1-/-CD4+T cells produced more cytokines than wild-type CD4+T cells in vitro, demonstrating an inhibitory role for PD-L1 on APCs and T cells. In vivo CD8+T cells responses also were significantly enhanced, indicating that PD-L1 has a role in limiting the expansion or survival of CD8+T cells. Studies using the myelin oligodendrocyte model of experimental autoimmune encephalomyelitis showed that PD-L1 on T cells and in host tissues limits responses of self-reactive CD4+T cells in vivo. PD-L1 deficiency converted the 129S4/SvJae strain from a resistant to experimental autoimmune encephalomyelitis-susceptible strain. Transfer of encephalitogenic T cells from wild-type mice into PD- L1-/-recipients led to exacerbated disease. Disease was even more severe in PD- L1-/-recipients of PD- L1-/-T cells. These results demonstrate that PD-L1 on T cells, APCs, and host tissue inhibits naïve and effector T cell responses and plays a critical role in T cell tolerance.