Cutting Edge: Murine Vascular Endothelium Activates and Induces the Generation of Allogeneic CD4+25+Foxp3+ Regulatory T Cells

Abstract

Unlike graft-resident donor-derived hemopoietic APCs, which decrease in number over time after transplantation, vascular endothelial cells are lifelong residents of a vascularized allograft. Endothelial cells are potent APCs for allogeneic CD8+ T lymphocytes but are unable to induce proliferation of allogeneic CD4+ T lymphocytes. Although the reason for this differential response has been poorly understood, here we report that alloantigen presentation by vascular endothelium to CD4+ T lymphocytes activates and induces CD4+25+Foxp3+ regulatory T cells, which can inhibit proliferation of alloreactive T cells both in vitro and in vivo. This process occurs independently of B7.1 costimulation but is dependent on programmed death ligand 1 (B7-H1). This finding may have important implications for tolerance induction in transplantation.

Clinical Significance and Therapeutic Potential of the Programmed Death Ligand-1 (PD-L1) and PD-L2 Expression in Human Colorectal Cancer

“…Interestingly we found further evidence from our analyzed colorectal cancers for co-expression of PD-1 on CD4/Foxp3-positive T cells. This indicates T regulatory cell-mediated mechanisms by which tumor cells can evade immune recognition and destruction [19,23]. These results are in accordance with the recent work by Masugi et al The authors had observed a significant inverse association of tumor PD-L1 expression with Foxp3+ cell density, but not with CD8+ T cell density, suggesting that the influence of tumor-mediated PD-L1 expression on T-cell densities vary in the different T cell subpopulations [22].…”

“…PD-L1 expressed on tumor cells increases apoptosis of antigen-specific T cell clones in vitro [18]. Furthermore, PD-L1 blockade with an anti-PD-L1 monoclonal antibody enhanced anti-tumor immunity and inhibited tumor growth in vivo [19]. Therefore, PD-L1 has been suggested to play an important role in immune evasion from the host immune system via PD-1-mediated inhibitory signals that give tumors advantage by selectively inhibiting CD8-positive T cells [13,20,21].…”

Immune Regulation by Microvascular Endothelial Cells: Directing Innate and Adaptive Immunity, Coagulation, and Inflammation

“…Alloantigen-specific CD8 ϩ CD28 Ϫ T suppressor cells induce expression of inhibitory receptors and down-regulate adhesion molecules on ECs, rendering them tolerogenic (44). In addition, alloantigen presentation by EC to CD4 ϩ T cells induces CD4 ϩ CD25 ϩ Foxp3 ϩ regulatory T cells capable of suppressing proliferation of alloreactive T cells in vitro and in vivo (45) (Fig. 1).…”

MHC Class II Antigen Presentation by Dendritic Cells Regulated through Endosomal Sorting

“…However, constitutive MHCII expression by non-APCs in the absence of costimulatory molecules, for example, by epithelial cells, has an important role in maintaining peripheral tolerance (Krupnick et al 2005;Kreisel et al 2010). Yet other cell types can be induced to express MHCII by certain stimuli, for example, by the cytokine IFN-g (Pober et al 1983;Geppert and Lipsky 1985;Romieu-Mourez et al 2007;Mulder et al 2011).…”