P-selectin glycoprotein ligand-1 mediates L-selectin-independent leukocyte rolling in high endothelial venules of peripheral lymph nodes

Abstract

Lymphocyte homing to peripheral lymph nodes (LNs) requires L-selectin. Previous studies, however, suggest that there are L-selectin-independent mechanisms of lymphocyte homing. P-selectin glycoprotein ligand-1 (PSGL-1) is a major ligand for P-selectin expressed in a selectin-binding form on myeloid cells and subsets of lymphoid cells. To discover whether PSGL-1 plays a role in lymphocyte homing, we examined leukocyte rolling and adhesion in the high endothelial venules (HEVs) of the subiliac LNs of wild-type and PSGL-1-deficient mice by intravital microscopy. There were no significant differences in blood velocity or wall shear stress between wild-type and PSGL-1-deficient mice. Although the leukocyte rolling fraction was not altered in PSGL-1-deficient mice, infusion of an anti-L-selectin mAb into these mice completely abolished leukocyte rolling, while the same treatment in wild-type mice inhibited 90% of the leukocyte rolling. This residual rolling in wild-type mice appears to depend on the PSGL-1-P-selectin interaction, since infusion of an anti-L-selectin mAb together with an anti-PSGL-1 mAb or anti-P-selectin mAb almost completely abolished the rolling. PSGL-1 deficiency also led to a higher rolling velocity, suggesting that PSGL-1 mediates leukocyte rolling at low velocities. P-selectin was found to be expressed on the HEVs of subiliac LNs under the conditions of intravital microscopy. Taken together, these results indicate that the interaction of PSGL-1 with P-selectin constitutes a second mechanism of leukocyte rolling in the HEVs of peripheral LNs.

Interleukin-15 enhances cellular proliferation and upregulates CNS homing molecules in pre-B acute lymphoblastic leukemia

“…34 The induction of PSGL-1 by IL-15 may alter leukocyte trafficking; PSGL-1 is a ligand for both L and P selectins, the major determinants of tethering and rolling in LN endothelial venules. 40 In addition, P-selectin/PSGL-1 interactions are important determinants of cellular passage across the blood-CSF barrier. 36 Our screen also identified the chemokine receptor CXCR3 and the protease SERPINE1 as inducible by IL-15.…”

Single and Coexpression of CXCR4 and CXCR5 Identifies CD4 T Helper Cells in Distinct Lymph Node Niches during Influenza Virus Infection

“…These data further show that the coexpression of CXCR4 and CXCR5 identifies T GC and suggest that germinal centers require X5 ϩ /X4 ϩ T GC . The adoptive transfer of wild-type X5 ϩ /X4 ϩ T FH from MedLN back into infected mice demonstrated their inability to enter lymph nodes (not shown), likely because they lack CD62L and PSGL-1, molecules that facilitate T cell migration through high endothelial venules (HEV) (4,15) (Fig. 2), further indicating their residence and function within secondary lymphoid tissues.…”

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.…”