Regulation of T cell activation and tolerance by PDL2

Abstract

T cell activation and tolerance are regulated by costimulatory molecules. Although PD-1 serves as a crucial negative regulator of T cells, the function of its ligands, PDL1 and PDL2, is still controversial. In this study, we created a PDL2-deficient mouse to characterize its function in T cell activation and tolerance. Antigenpresenting cells from PDL2؊͞؊ mice were found to be more potent in activation of T cells in vitro over the wild-type controls, which depended on PD-1. Upon immunization with chicken ovalbumin, PDL2؊͞؊ mice exhibited increased activation of CD4 ؉ and CD8 ؉ T cells in vivo when compared with WT animals. In addition, T cell tolerance to an oral antigen was abrogated by the lack of PDL2. Our results thus demonstrate that PDL2 negatively regulates T cells in immune responses and plays an essential role in immune tolerance.costimulation ͉ cytokines ͉ PD-1 D uring infection, pathogen-specific T cells are activated, undergo robust clonal expansion, and subsequently differentiate into effector cells. In contrast, peripheral tolerance mechanisms have been found to prevent autoreactive T cell function (1, 2). Oral tolerance is a form of peripheral tolerance, in which antigen-specific T cell tolerance is induced against oral antigens (3). Although oral tolerance has been tested for protection against autoimmune and allergic diseases, the cellular and molecular mechanisms underlying oral tolerance induction have remained unclear.T cell activation and tolerance are critically regulated by costimulatory molecules, especially those in the B7 and CD28 superfamilies (4). PD-1, a novel member of the CD28 family, is expressed on activated T cells and B cells (5). PD-1 has been shown to be a negative regulator of T cell activation and is crucial for maintaining immune tolerance. PD-1 deficiency in mouse results in spontaneous autoimmune diseases (6, 7). Moreover, PD-1 deficiency (8) or blockade (9) accelerated autoimmune diabetes on NOD background. Blocking PD-1 also enhanced experimental autoimmune encephalomyelitis (EAE) disease (10).Two ligands, B7-H1͞PDL1 and PDL2͞B7DC, have been found to bind to . The function of PDL1 and PDL2 in T cell activation is still in debate. Contradictory results have suggested PDL2 serves as a negative and a positive regulator of T cell function. Latchman et al. (13) have shown that recombinant PDL2 protein inhibited the activation and cytokine production of CD4 ϩ T cells via cell-cycle arrest, whereas Tseng et al. (14) published that B7DC-Ig costimulated the proliferation of naïve T cells at suboptimal anti-CD3 concentrations, and that it increased IFN-␥ secretion. Others studied PDL2 function by using antibodies that block PDL2 binding to PD-1. Salama et al. (10) reported exacerbation of EAE disease when PDL2, but not PDL1, was blocked. In a model of airway hypersensitivity, Matsumoto et al. (15) found that anti-PDL2 antibody administered at the time of challenge increased eosinophilia. These data suggest that PDL2, through engaging PD-1, negatively regulates T cell priming...

Cutting Edge: Programed Death (PD) Ligand-1/PD-1 Interaction Is Required for CD8+ T Cell Tolerance to Tissue Antigens

“…Our results thus agree on the roles of PD-1 and PD-L1 as negative costimulatory molecules in T1D as described by others (15)(16)(17). Interestingly, PD-L2 was recently found to be important in CD4 ϩ T cell tolerance to oral Ags (26). Impairments of an immune tolerance mechanism regulated by PD-1 could thus lead to susceptibility to autoimmunity, while inhibiting PD-1 may be explored in the boosting of immunity to infectious agents and to cancer.…”

The Kidney-Renal Lymph Node-System Contributes to Cross-Tolerance against Innocuous Circulating Antigen

“…Although an additional effect of anergy cannot be formally excluded, these results demonstrate that the observed decline of OT-I cells activated by filterable Ag resulted to a great extent from deletion. The mechanisms inducing such tolerance remain to be identified, but may be related to the selective expression of B7-DC (PD-L2), which negatively regulates T cell activation (44,45), on DCs carrying filterable Ag. Alternative to deletion, it is possible that regulatory CD4 ϩ T cells were induced and contributed to tolerance against filterable Ag.…”

“…After 5 days, the spleens and LNs from secondary recipient mice were taken and analyzed for surviving Thy1. spleen expressed more B7-DC (PD-L2), a negative regulator of T cell activation (44,45), than other DCs (Fig. 9).…”

MicroPath-A pathway-based pipeline for the comparison of multiple gene expression profiles to identify common biological signatures

“…Further studies have correlated the over-expression of this gene to the negative regulation of T-cell activation. In one particular study, PDL2 (Pdcd1lg2) deficient mice were created in order to characterise the function of this gene in T-cell activation and tolerance, and results generated from this study suggested that Antigen-presenting cells from PDL2-deficient mice were found to be more potent in activating T-cells in vitro when compared to the wild-type counterparts [22]. These findings are conclusive and correlate well with the results generated from our in-house microarray experiments because using MicroPath to compare all three of our datasets followed by extracting gene expression patterns from them resulted in an important finding that Pdcd1lg2 was not only found to be over-expressed in tolerance (fold change of 3.921), but it was also under-expressed in our KOA0 Vs WTA0 and KOA6 Vs WTA6 knock-out datasets (with a fold change of 1.140 and 0.079 respectively) ( Table 2).…”