Interaction between B7-H1 and PD-1 determines initiation and reversal of T-cell anergy

Abstract

IntroductionInteraction of receptors and ligands between T cells and antigenpresenting cells (APCs) is a very early event for transmitting signals to control T-cell growth, differentiation, tolerance, and death. 1 For example, cytotoxic T lymphocyte (CTL)-associated antigen 4 (CTLA-4), which is rapidly up-regulated on activated T cells and delivers an inhibitory signal to T cells upon binding to CD80/CD86, antagonizes CD28 costimulation and maintains T-cell homeostasis and selftolerance. 2 CTLA-4 signaling, however, is not required for T-cell anergy. 3 Recent studies have established a critical role in T-cell regulation of a new molecular pathway involving B7-H1, B7-DC, and their receptor PD-1. 1,3 PD-1 is inducible on activated T, B, and myeloid cells. 4 PD-1 knockout (KO) mice develop systemic and organ-specific autoimmune diseases. 5,6 Therefore, PD-1 may play an essential role in suppression of autoimmunity and inflammation. B7-H1 is constitutively expressed in a fraction of dendritic cells (DCs) and macrophages, and cell-surface B7-H1 could be up-regulated in virtually all nucleated cells by inflammatory cytokines, including interferons. 7,8 In contrast, the expression of B7-DC is restricted to DCs and activated macrophages. 9,10 The exact role of B7-DC in the regulation of adaptive immunity and inflammation has yet to be clarified because it displays both positive and negative effects on T-cell activation, depending on the systems used. 1,3 There is ample evidence supporting the idea that, in peripheral tissues, B7-H1 is a dominant ligand for PD-1-mediated inhibition of effector T-cell function. 1,3 Several independent mechanisms underlying suppression of T-cell responses by B7-H1/PD-1 include deletion/apoptosis, 8,11 resistance to lysis, 12,13 growth inhibition, 14 and generation and maintenance of T-cell exhaustion. 15 Several studies also reveal an association of elevated expression of B7-H1 and PD-1 with disease progression, T-cell suppression, exhaustion, and death during HIV infection. [16][17][18][19] While the suppressive effect of PD-1 on execution of effector T-cell functions in peripheral organs is well documented, its role in making early decisions related to tolerance induction among naive or recently primed T cells is unknown. This requires early analysis of T-cell phenotype and function after exposure to tolerogen prior to exit from lymphoid organs. We used a classic in vivo system of T-cell anergy whereby naive CD8 ϩ OT-1 T-cell receptor (TCR) transgenic T cells are transferred into B6 mice. 20 OT-1 T cells specifically recognize a peptide encoding an H-2K b -restricted epitope of chicken ovalbumin (OVA). Virtually all transferred OT-1 T cells are engaged by antigen after intravenous administration of excess amounts of soluble OVA peptide without adjuvant as a tolerogen (0.5 mg/mouse). As a result, OT-1 T cells expand vigorously and reach up to 20% of total CD8 ϩ cells in the spleen within 3 days. After reaching a peak at day 4 or 5, T-cell numbers contract dramatically due to apoptosis. Wh...

Premature Terminal Exhaustion of Friend Virus-Specific Effector CD8+ T Cells by Rapid Induction of Multiple Inhibitory Receptors

“…These observations strikingly resemble the early events in FV infection, which is represented by the rapid expansion of virus-infected, PD-L1 Hi erythroblasts and rapid exhaustion of CD8 + T cells, although the severity of virus infection and CD8 + T cell exhaustion between these models differs in degree. Considering that CD8 + T cells upregulate inhibitory molecules at very early stages under the tolerogenic environment and that the negative signals provided at this stage have a profound impact on the early fate-decision of CD8 + T cells (44,58), prevention of the potential negative signals during the priming/differentiation phase is rational for rescuing virus-specific CD8 + T cells from terminal exhaustion and for the effective elimination of virus-infected cells, as we successfully demonstrated in the current study.…”

Mucosal-Associated Invariant T Cell Deficiency in Systemic Lupus Erythematosus

“…In conventional T cells, PD-1 is not expressed on naive T cells, but it is inducibly expressed after T cell activation (36). In recent reports, PD-1 and its ligands have been implicated in the induction and maintenance of T cell and NKT cell anergy (37,38,42,43). In our previous report, we demonstrated that NKT cell dysfunction was associated with upregulation of inhibitory receptor PD-1 in active tuberculosis, and it was partially recovered by blockade of PD-1 (44).…”

Reviving Function in CD4+ T Cells Adapted to Persistent Systemic Antigen

“…Blockade of PD-L1 also accelerated GVHD disease lethality in irradiated bone marrow recipients (35). PD-1/PD-L1 appeared also to be responsible for the induction and the maintenance of T cell unresponsiveness in an in vivo model of functional anergy in TCRtransgenic T cells induced by high doses of antigenic peptide (36). The other prototype of CD28 family inhibitory receptors is CTLA-4 (CD152) (37).…”