Functional Role of P-Selectin Glycoprotein Ligand 1/P-Selectin Interaction in the Generation of Tolerogenic Dendritic Cells

Abstract

Dendritic cells (DCs) have a key role in both the generation of the immune response and the induction of tolerance to self-Ags. In this work, the possible role of P-selectin glycoprotein ligand 1 (PSGL-1) on the tolerogenic activity of human DCs was explored. We found that the engagement of PSGL-1 by P-selectin on DCs induced the expression of c-Fos, IDO, IL-10, and TGF-β genes. Remarkably, stimulation of DCs through PSGL-1 with P-selectin enhanced their capability to generate CD4+CD25+Foxp3+ regulatory T cells, which expressed high levels of TGF-β1 mRNA, synthesized IL-10, and suppressed the proliferation of autologous CD4+CD25− T cells. Accordingly, we found that DCs from PSGL-1−/− mice expressed higher levels of MHC class II molecules, and exhibited an enhanced immunogenicity compared with wild-type mice. In addition, the percentage of CD4+CD25+Foxp3+ regulatory T cells in the thymus of PSGL-1-deficient animals was significantly reduced. Our data reveal an unexpected role of PSGL-1 on the tolerogenic function of DCs, and the regulation of the immune response.

An evolutionary history of the selectin gene cluster in humans

“…Interestingly, the interaction of SELP with SELPLG has been shown to contribute to the generation of tolerogenic dendritic cells (Urzainqui et al, 2007), and P-selectin binding to pentraxin 3 activates a negative feed-back loop that decreases leukocyte recruitment at inflammation sites (Deban et al, 2010). In line with these observations and with its role in immune responses, polymorphisms in SELP have been associated with autoimmune manifestations or chronic inflammatory diseases.…”

Leukocyte ligands for endothelial selectins: specialized glycoconjugates that mediate rolling and signaling under flow

“…38,87 Why receptor translation along the membrane is controlled by CD44 but not PSGL-1 is unknown. There is also evidence that engagement of PSGL-1 by P-selectin or E-selectin can trigger proliferative and differentiation signals in hematopoietic cells, including hematopoietic progenitors 88 and dendritic cells, 89 with functional consequences during inflammation. 90 The signaling pathways controlling these processes have not been described.…”

The metalloprotease ADAM8 is associated with and regulates the function of the adhesion receptor PSGL‐1 through ERM proteins

“…P-selectin glycoprotein ligand-1 (PSGL-1), through its interaction with P-, E-and L-selectins, mediates the tethering and rolling of leukocytes on endothelial cells prior to their extravasation [9,10], triggers the activation of transcription factors like cFos [11] in leukocytes and induces the generation of tolerogenic DCs which promote the differentiation of Treg cells [12]. Although it was described that PSGL-1 was a substrate of the proteases BACE1 and ADAM10 [13], neither the physiological context of cleavage nor the mechanism responsible for its shedding have been identified so far.…”

“…It has been described that ADAM8 cleaves important cell surface proteins [3,4], cytokines and growth factors [5]. ADAM8 is overexpressed under several pathological conditions involving inflammation and remodeling of the extracellular matrix, including malignant diseases and asthma [6][7][8].P-selectin glycoprotein ligand-1 (PSGL-1), through its interaction with P-, E-and L-selectins, mediates the tethering and rolling of leukocytes on endothelial cells prior to their extravasation [9,10], triggers the activation of transcription factors like cFos [11] in leukocytes and induces the generation of tolerogenic DCs which promote the differentiation of Treg cells [12]. Although it was described that PSGL-1 was a substrate of the proteases BACE1 and ADAM10 [13], neither the physiological context of cleavage nor the mechanism responsible for its shedding have been identified so far.…”