scholarly journals The S1P-analog FTY720 differentially modulates T-cell homing via HEV: T-cell–expressed S1P1 amplifies integrin activation in peripheral lymph nodes but not in Peyer patches

Blood ◽  
2005 ◽  
Vol 106 (4) ◽  
pp. 1314-1322 ◽  
Author(s):  
Cornelia Halin ◽  
M. Lucila Scimone ◽  
Roberto Bonasio ◽  
Jean-Marc Gauguet ◽  
Thorsten R. Mempel ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Integrin Activation ◽  
High Endothelial Venules ◽  
Peripheral Lymph ◽  
Sphingosine 1 Phosphate ◽  
T Cell Homing ◽  
Prolonged Retention ◽  
Lymphocyte Egress

AbstractSphingosine-1-phosphate (S1P) and its receptor S1P1 control T-cell egress from thymus and secondary lymphoid organs (SLOs). To further define the role of S1P1 in lymphocyte trafficking, we performed adoptive transfer experiments and intravital microscopy (IVM) using both S1P1–/– lymphocytes and recipient wild-type (WT) mice treated with FTY720, an immunosuppressant that downmodulates S1P receptors. S1P1 deficiency and FTY720 caused rapid disappearance of T cells from blood, prolonged retention in SLOs, and accumulation in bone marrow, but did not alter interstitial T-cell motility in peripheral lymph nodes (PLNs) as assessed by multiphoton IVM. However, S1P1–/– lymphocytes displayed reduced short-term homing to PLNs due to attenuated integrin-mediated firm arrest in high endothelial venules (HEVs). By contrast, S1P1–/– T cells homed normally to Peyer patches (PPs), whereas S1P1–/– B cells had a marked defect in homing to PPs and arrested poorly in PP HEVs. Therefore, S1P1 not only controls lymphocyte egress from SLOs, but also facilitates in a tissue- and subset-specific fashion integrin activation during homing. Interestingly, FTY720 treatment enhanced accumulation of both S1P1 sufficient and S1P1–/– T cells in PPs by enhancing integrin-mediated arrest in HEVs. Thus, FTY720 exerts unique effects on T-cell traffic in PPs that are independent of T-cell–expressed S1P1.

Core 2 branching β1,6-N-acetylglucosaminyltransferase and high endothelial cell N-acetylglucosamine-6-sulfotransferase exert differential control over B- and T-lymphocyte homing to peripheral lymph nodes

Blood ◽  
2004 ◽  
Vol 104 (13) ◽  
pp. 4104-4112 ◽  
Author(s):  
Jean-Marc Gauguet ◽  
Steven D. Rosen ◽  
Jamey D. Marth ◽  
Ulrich H. von Andrian
Keyword(s):  
T Cells ◽  
Endothelial Cell ◽  
T Cell ◽  
B Cells ◽  
Lymph Nodes ◽  
B Cell ◽  
Lymphocyte Homing ◽  
High Endothelial Venules ◽  
Rolling Velocity ◽  
Peripheral Lymph

Abstract Blood-borne lymphocyte trafficking to peripheral lymph nodes (PLNs) depends on the successful initiation of rolling interactions mediated by L-selectin binding to sialomucin ligands in high endothelial venules (HEVs). Biochemical analysis of purified L-selectin ligands has identified posttranslational modifications mediated by Core2GlcNAcT-I and high endothelial cell GlcNAc-6-sulfotransferase (HECGlcNAc6ST). Consequently, lymphocyte migration to PLNs of C2GlcNAcT-I-/- and HEC-GlcNAc6ST-/- mice was reduced; however, B-cell homing was more severely compromised than T-cell migration. Accordingly, intravital microscopy (IVM) of PLN HEVs revealed a defect in B-cell tethering and increased rolling velocity (Vroll) in C2GlcNAcT-I-/- mice that was more pronounced than it was for T cells. By contrast, B- and T-cell tethering was normal in HEC-GlcNAc6ST-/- HEVs, but Vroll was accelerated, especially for B cells. The increased sensitivity of B cells to glycan deficiencies was caused by lower expression levels of L-selectin; L-selectin+/- T cells expressing L-selectin levels equivalent to those of B cells exhibited intravascular behavior similar to that of B cells. These results demonstrate distinct functions for C2GlcNAcT-I and HEC-GlcNAc6ST in the differential elaboration of HEV glycoproteins that set a threshold for the amount of L-selectin needed for lymphocyte homing. (Blood. 2004;104:4104-4112)

scholarly journals CD40L+ CD4+ memory T cells migrate in a CD62P-dependent fashion into reactive lymph nodes and license dendritic cells for T cell priming

2008 ◽  
Vol 205 (11) ◽  
pp. 2561-2574 ◽  
Author(s):  
Alfonso Martín-Fontecha ◽  
Dirk Baumjohann ◽  
Greta Guarda ◽  
Andrea Reboldi ◽  
Miroslav Hons ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Memory T Cells ◽  
Effector Memory ◽  
High Endothelial Venules ◽  
T Cell Priming ◽  
Dc Maturation

There is growing evidence that the maturation state of dendritic cells (DCs) is a critical parameter determining the balance between tolerance and immunity. We report that mouse CD4+ effector memory T (TEM) cells, but not naive or central memory T cells, constitutively expressed CD40L at levels sufficient to induce DC maturation in vitro and in vivo in the absence of antigenic stimulation. CD4+ TEM cells were excluded from resting lymph nodes but migrated in a CD62P-dependent fashion into reactive lymph nodes that were induced to express CD62P, in a transient or sustained fashion, on high endothelial venules. Trafficking of CD4+ TEM cells into chronic reactive lymph nodes maintained resident DCs in a mature state and promoted naive T cell responses and experimental autoimmune encephalomyelitis (EAE) to antigens administered in the absence of adjuvants. Antibodies to CD62P, which blocked CD4+ TEM cell migration into reactive lymph nodes, inhibited DC maturation, T cell priming, and induction of EAE. These results show that TEM cells can behave as endogenous adjuvants and suggest a mechanistic link between lymphocyte traffic in lymph nodes and induction of autoimmunity.

scholarly journals The Strategy of T Cell Antigen-presenting Cell Encounter in Antigen-draining Lymph Nodes Revealed by Imaging of Initial T Cell Activation

2003 ◽  
Vol 198 (5) ◽  
pp. 715-724 ◽  
Author(s):  
Marc Bajénoff ◽  
Samuel Granjeaud ◽  
Sylvie Guerder
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
T Cell Activation ◽  
Cell Activation ◽  
Strategic Positioning ◽  
High Endothelial Venules ◽  
Rare Cells ◽  
Antigen Presenting

The development of an immune response critically relies on the encounter of rare antigen (Ag)-specific T cells with dendritic cells (DCs) presenting the relevant Ag. How two rare cells find each other in the midst of irrelevant other cells in lymph nodes (LNs) is unknown. Here we show that initial T cell activation clusters are generated near high endothelial venules (HEVs) in the outer paracortex of draining LNs by retention of Ag-specific T cells as they exit from HEVs. We further show that tissue-derived DCs preferentially home in the vicinity of HEVs, thus defining the site of cluster generation. At this location DCs efficiently scan all incoming T cells and selectively retain those specific for the major histocompatibility complex–peptide complexes the DCs present. Such strategic positioning of DCs on the entry route of T cells into the paracortex may foster T cell–DC encounter and thus optimize initial T cell activation in vivo.

Facial Nerve Transection Causes Expansion of Myelin Autoreactive T Cells in Regional Lymph Nodes and T Cell Homing to the Facial Nucleus

Autoimmunity ◽  
1992 ◽  
Vol 13 (2) ◽  
pp. 117-126 ◽  
Author(s):  
Tomas Olsson ◽  
Per Diener ◽  
Åke Ljungdahl ◽  
Bo Höjeberg ◽  
Peter H. Van Der Meide ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Facial Nerve ◽  
Lymph Nodes ◽  
Nerve Transection ◽  
Facial Nucleus ◽  
Regional Lymph Nodes ◽  
Autoreactive T Cells ◽  
Cell Homing ◽  
T Cell Homing

scholarly journals LFA-1 blockade induces effector and regulatory T-cell enrichment in lymph nodes and synergizes with CTLA-4Ig to inhibit effector function

Blood ◽  
2011 ◽  
Vol 118 (22) ◽  
pp. 5851-5861 ◽  
Author(s):  
Natalie M. Reisman ◽  
Tamara L. Floyd ◽  
Maylene E. Wagener ◽  
Allan D. Kirk ◽  
Christian P. Larsen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Lymph Nodes ◽  
Therapeutic Potential ◽  
Solid Organ Transplantation ◽  
Solid Organ ◽  
Relative Distribution ◽  
Lymphocyte Function ◽  
Peripheral Lymph

Abstract Despite encouraging results using lymphocyte function antigen-1 (LFA-1) blockade to inhibit BM and solid organ transplantation rejection in nonhuman primates and humans, the precise mechanisms underlying its therapeutic potential are still poorly understood. Using a fully allogeneic murine transplantation model, we assessed the relative distribution of total lymphocyte subsets in untreated versus anti–LFA-1–treated animals. Our results demonstrated a striking loss of naive T cells from peripheral lymph nodes, a concomitant gain in blood after LFA-1 blockade, and a shift in phenotype of the cells remaining in the node to a CD62LloCD44hi profile. We determined that this change was due to a specific enrichment of activated, graft-specific effectors in the peripheral lymph nodes of anti–LFA-1–treated mice compared with untreated controls, and not to a direct effect of anti–LFA-1 on CD62L expression. LFA-1 blockade also resulted in a dramatic increase in the frequency of CD4+ FoxP3+ regulatory T cells in graft-draining nodes. Our results suggest that the differential impact of LFA-1 blockade on the distribution of naive versus effector and regulatory T cells may underlie its ability to inhibit alloreactive T-cell responses after transplantation.

scholarly journals Dynamin 2–dependent endocytosis is required for sustained S1PR1 signaling

2014 ◽  
Vol 211 (4) ◽  
pp. 685-700 ◽  
Author(s):  
Tim Willinger ◽  
Shawn M. Ferguson ◽  
João P. Pereira ◽  
Pietro De Camilli ◽  
Richard A. Flavell
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
Lymph Nodes ◽  
Knockout Mice ◽  
Lymphoid Organs ◽  
Essential Component ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor ◽  
Lymphocyte Egress ◽  
Dynamin 2

Sphingosine-1-phosphate (S1P) receptor 1 (S1PR1) is critical for lymphocyte egress from lymphoid organs. Lymphocytes encounter low S1P concentrations near exit sites before transmigration, yet S1PR1 signaling is rapidly terminated after exposure to S1P. How lymphocytes maintain S1PR1 signaling in a low S1P environment near egress sites is unknown. Here we identify dynamin 2, an essential component of endocytosis, as a novel regulator of T cell egress. Mice with T cell–specific dynamin 2 deficiency had profound lymphopenia and impaired egress from lymphoid organs. Dynamin 2 deficiency caused impaired egress through regulation of S1PR1 signaling, and transgenic S1PR1 overexpression rescued egress in dynamin 2 knockout mice. In low S1P concentrations, dynamin 2 was essential for S1PR1 internalization, which enabled continuous S1PR1 signaling and promoted egress from both thymus and lymph nodes. In contrast, dynamin 2–deficient cells were only capable of a pulse of S1PR1 signaling, which was insufficient for egress. Our results suggest a possible mechanism by which T lymphocytes positioned at exit portals sense low S1P concentrations, promoting their egress into circulatory fluids.

scholarly journals PI3K in T Cell Adhesion and Trafficking

2021 ◽  
Vol 12 ◽  
Author(s):  
Kristoffer H. Johansen ◽  
Dominic P. Golec ◽  
Julie H. Thomsen ◽  
Pamela L. Schwartzberg ◽  
Klaus Okkenhaug
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Mouse Models ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Cell Trafficking ◽  
High Endothelial Venules ◽  
Cell Functions ◽  
And Function

PI3K signalling is required for activation, differentiation, and trafficking of T cells. PI3Kδ, the dominant PI3K isoform in T cells, has been extensively characterised using PI3Kδ mutant mouse models and PI3K inhibitors. Furthermore, characterisation of patients with Activated PI3K Delta Syndrome (APDS) and mouse models with hyperactive PI3Kδ have shed light on how increased PI3Kδ activity affects T cell functions. An important function of PI3Kδ is that it acts downstream of TCR stimulation to activate the major T cell integrin, LFA-1, which controls transendothelial migration of T cells as well as their interaction with antigen-presenting cells. PI3Kδ also suppresses the cell surface expression of CD62L and CCR7 which controls the migration of T cells across high endothelial venules in the lymph nodes and S1PR1 which controls lymph node egress. Therefore, PI3Kδ can control both entry and exit of T cells from lymph nodes as well as the recruitment to and retention of T cells within inflamed tissues. This review will focus on the regulation of adhesion receptors by PI3Kδ and how this contributes to T cell trafficking and localisation. These findings are relevant for our understanding of how PI3Kδ inhibitors may affect T cell redistribution and function.

NK Cells Induce Alloreactive Donor T Cell Apoptosis and Decrease Proliferation in GVHD Induction.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2162-2162
Author(s):  
Janelle A. Olson ◽  
Dennis B. Leveson-Gower ◽  
Andreas Beilhack ◽  
Robert S. Negrin
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Nk Cells ◽  
Nk Cell ◽  
Cell Trafficking ◽  
Peripheral Lymph ◽  
Donor T Cells

Abstract Natural Killer (NK) cells have the ability to suppress graft-versus-host disease (GVHD) while inducing a graft-versus-tumor response (GVT) during allogeneic bone marrow transplantation (BMT). Previous studies in allogeneic BMT models have shown NK cell trafficking to and proliferation in lymphoid organs and GVHD target organs, which are also sites of donor T cell trafficking. This study aims to investigate the impact of NK cells on alloreactive, GVHD-inducing donor T cells. Interleukin-2 activated allogeneic NK cells isolated from C57Bl6 (H–2b) or FVB (H–2q) animals were transplanted along with T cell-depleted bone marrow into lethally irradiated BALB/c (H–2d) mice, followed 2 days later by luciferase-expressing CD4+ and CD8+ conventional T cells from the same donor strain (NK+Tcon group). Control mice received lethal irradiation and T cell-depleted bone marrow on day 0, and luciferase-expressing T cells on day 2 after transplant (Tcon group). Bioluminescence imaging of NK+Tcon mice revealed a significantly lower T cell bioluminescent signal (p=0.03 for FVB into BALB/c on day 6) than from Tcon mice. CFSE proliferation analysis of alloreactive T cells on day 3 after transplant showed no significant change in the percent of donor T cells that have divided in the spleen, and only a slight decrease in the percent of T cells that have divided in the lymph nodes when NK cells are present. However, at this timepoint 82% of the proliferating cells have divided past the third generation, in contrast to 64% in the NK+Tcon mice. Donor T cells in both groups become equally activated in vivo, expressing similar levels of the early-activation marker CD69. T cells re-isolated from NK+Tcon animals at day 5 stained 2 to 10-fold higher for the TUNEL apoptosis marker than those from Tcon mice in the mesenteric and peripheral lymph nodes, respectively (p<0.0001). Additionally, decreased numbers of T cells were re-isolated from the peripheral lymph nodes in the NK+Tcon group as compared to the Tcon group. This increase in TUNEL staining was not seen when the transplanted NK cells were isolated from a perforin-deficient donor. This indicates that NK cells in lymph nodes use a perforin-dependent mechanism to increase apoptosis in proliferating, alloreactive donor T-cells, which are syngeneic to the transplanted NK cells. Donor T cells re-isolated from the lymph nodes of transplanted mice up-regulate the NKG2D ligand Rae1γ as compared to naïve T cells, as shown by FACS. This suggests that NK cells may cause direct lysis of alloreactive donor T cells in vivo during GVHD induction, mediated by the NK cell activating receptor NKG2D. This study provides crucial mechanistic information regarding the function of NK cells in suppressing GVHD.

scholarly journals The Route of Antigen Entry Determines the Requirement for L-selectin during Immune Responses

1996 ◽  
Vol 184 (6) ◽  
pp. 2341-2352 ◽  
Author(s):  
Michelle D. Catalina ◽  
Michael C. Carroll ◽  
Helen Arizpe ◽  
Akira Takashima ◽  
Pila Estess ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Nodes ◽  
Contact Hypersensitivity ◽  
Targeted Disruption ◽  
High Endothelial Venules ◽  
Peripheral Lymph ◽  
Successful Execution ◽  
Alternate Routes ◽  
Deficient Mice

L-selectin, an adhesion molecule constitutively expressed on leukocytes, is important for primary adhesion and extravasation of lymphocytes at specialized high endothelial venules within lymph nodes and other leukocytes at sites of inflammation. We have generated L-selectin–deficient mice by targeted disruption, and have confirmed a previously reported phenotype which includes strikingly impaired contact hypersensitivity (CHS) responses to reactive haptens (Tedder, T.F., D.A. Steeber, and P. Pizcueta. 1995. J. Exp. Med. 181:2259–2264; Xu, J.C., I.S. Grewal, G.P. Geba, and R.A. Flavell. 1996. 183:589–598.). Since the mechanism of this impairment has not been clarified, we sought to define the stage(s) at which the CHS response is affected in L-selectin–deficient mice. We show that epidermal Langerhans cells in L-selectin– deficient mice are normal in number, migrate to peripheral lymph nodes appropriately, and are functional in presenting allogeneic and haptenic antigens. Moreover, T cells, as well as neutrophil and monocyte effector populations, are fully capable of entry into the inflamed skin sites in the absence of L-selectin. Thus, antigen presentation and effector mechanisms are intact in L-selectin deficient mice. In contrast, virtually no antigen-specific T cells can be found within draining peripheral nodes after a contact challenge, suggesting that the defect resides primarily in the inability of antigen-specific T cells to home to and be activated in these nodes. Indeed, L-selectin–deficient mice mount completely normal CHS responses when alternate routes of immunization are used. These studies pinpoint the lesion in CHS to a discrete stage of the afferent limb of the response, clarify the role of L-selectin on effector populations, and illustrate the critical importance of the route of antigen entry to the successful execution of an immune response.

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