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.

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 Role of Phosphodiesterase 7 (PDE7) in T Cell Activity. Effects of Selective PDE7 Inhibitors and Dual PDE4/7 Inhibitors on T Cell Functions

2020 ◽  
Vol 21 (17) ◽  
pp. 6118 ◽  
Author(s):  
Marianna Szczypka
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Splice Variants ◽  
Cell Activity ◽  
Cell Functions ◽  
Simultaneous Inhibition ◽  
And Function

Phosphodiesterase 7 (PDE7), a cAMP-specific PDE family, insensitive to rolipram, is present in many immune cells, including T lymphocytes. Two genes of PDE7 have been identified: PDE7A and PDE7B with three or four splice variants, respectively. Both PDE7A and PDE7B are expressed in T cells, and the predominant splice variant in these cells is PDE7A1. PDE7 is one of several PDE families that terminates biological functions of cAMP—a major regulating intracellular factor. However, the precise role of PDE7 in T cell activation and function is still ambiguous. Some authors reported its crucial role in T cell activation, while according to other studies PDE7 activity was not pivotal to T cells. Several studies showed that inhibition of PDE7 by its selective or dual PDE4/7 inhibitors suppresses T cell activity, and consequently T-mediated immune response. Taken together, it seems quite likely that simultaneous inhibition of PDE4 and PDE7 by dual PDE4/7 inhibitors or a combination of selective PDE4 and PDE7 remains the most interesting therapeutic target for the treatment of some immune-related disorders, such as autoimmune diseases, or selected respiratory diseases. An interesting direction of future studies could also be using a combination of selective PDE7 and PDE3 inhibitors.

Costimulation of  T cells by B7-H2, a B7-like molecule that binds ICOS

Blood ◽  
2000 ◽  
Vol 96 (8) ◽  
pp. 2808-2813 ◽  
Author(s):  
Shengdian Wang ◽  
Gefeng Zhu ◽  
Andrei I. Chapoval ◽  
Haidong Dong ◽  
Koji Tamada ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chinese Hamster Ovary Cells ◽  
Chinese Hamster ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Ovary Cells ◽  
Inducible Costimulator ◽  
Immature Dendritic Cells ◽  
Dose Dependent

Abstract This report describes a new human B7-like gene designatedB7-H2. Cell surface expression of B7-H2 protein is detected in monocyte-derived immature dendritic cells. Soluble B7-H2 and immunoglobulin (Ig) fusion protein, B7-H2Ig, binds activated but not resting T cells and the binding is abrogated by inducible costimulator Ig (ICOSIg), but not CTLA4Ig. In addition, ICOSIg stains Chinese hamster ovary cells transfected with B7-H2 gene. By suboptimal cross-linking of CD3, costimulation of T-cell proliferation by B7-H2Ig is dose-dependent and correlates with secretion of interleukin (IL)-2, whereas optimal CD3 ligation preferentially stimulates IL-10 production. The results indicate that B7-H2 is a putative ligand for the ICOS T-cell molecule.

scholarly journals DIFFERENTIATION OF T-CELL PRECURSORS IN NUDE MICE DEMONSTRATED BY IMMUNOFLUORESCENCE OF T-CELL MEMBRANE MARKERS

1973 ◽  
Vol 138 (5) ◽  
pp. 1044-1055 ◽  
Author(s):  
F. Loor ◽  
B. Kindred
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Membrane ◽  
Lymph Nodes ◽  
Nude Mouse ◽  
T Lymphocyte ◽  
Nude Mice ◽  
Cell Functions ◽  
Spleen And Lymph Nodes ◽  
T Cell Membrane

When the thymus from an AKR mouse (TL-, θ-AKR) is grafted to a BALB/c-nu/nu mouse (TL2, θ-C3H), the grafted thymus is rapidly repopulated by host lymphocytes, i.e., lymphocytes having the TL2 and θ-C3H T-lymphocyte membrane antigen markers. θ-C3H lymphocytes also appear rapidly in the spleen and lymph nodes. After a few weeks, BALB/c nude mice grafted with AKR thymus and normal BALB/c mice could not be distinguished on the basis of the number of TL-positive thymocytes or θ-C3H-positive lymphocytes in thymus, spleen, or lymph nodes. These experiments give a definitive proof of the existence of precursor cells for the T compartment of the lymphoid system in the nude mouse. They strongly suggest the involvement of host-derived T cells in the recovery of some T-cell functions by nude mice grafted with allogeneic thymuses.

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.

Identification of a T cell lineage-specific RNA/DNA helicase and its cell surface expression during intrathymic education of αβ and γδ T cells

1997 ◽  
Vol 27 (12) ◽  
pp. 3269-3282 ◽  
Author(s):  
Arkadiusz Miazek ◽  
Manfred Brockhaus ◽  
Hanno Langen ◽  
Andrea Braun ◽  
Pawel Kisielow
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Surface ◽  
Cell Lineage ◽  
Γδ T Cells ◽  
Surface Expression ◽  
Dna Helicase ◽  
Cell Surface Expression

scholarly journals Immune checkpoint expression on HIV-specific CD4+ T cells and response to their blockade are dependent on lineage and function

2021 ◽  
Author(s):  
Elsa Brunet-Ratnasingham ◽  
Antigoni Morou ◽  
Mathieu Dube ◽  
Julia Niessl ◽  
Amy E. Baxter ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Immune Checkpoints ◽  
Chronic Infections ◽  
Cell Functions ◽  
Art Initiation ◽  
Specific Regulation ◽  
And Function

Background: Antigen-specific T cell impairment is observed in chronic infections. CD4+ T cells are diverse in phenotype and function; how their different lineages are impacted by inhibitory immune checkpoints (IC) is unknown. Methods: We examined IC expression and function in HIV-specific CD4+ T cells of viremic individuals prior to ART initiation and persons with spontaneous or therapy-induced viral suppression. We investigated IC patterns associated with exhaustion-related transcription factors and chemokine receptors using cytokine-independent activation-induced marker assays. We determined effector functions representative of TFH, TH1 and TH17/TH22 using ultra-sensitive RNA flow cytometric fluorescence in situ hybridization (FISH), and their response to IC blockade. Findings: The dysfunction-related transcription factor TOX was elevated in HIV-specific CD4+ T cells of viremic patients, and its expression was associated with lineage differentiation. We observed a hierarchy of PD-1, TIGIT and CD200 expression associated with both infection status and effector profile. In vitro responsiveness to PD-L1 blockade varied with defined CD4+ T cell functions rather than IC expression levels: frequencies of cells with TH1- and TH17/TH22-, but not TFH-related functions, increased. Response to PD-L1 blockade was strongest in viremic participants and reduced after ART initiation. Interpretation: Our data highlight a polarization-specific regulation of IC expression and differing sensitivities of antigen-specific Thelper subsets to PD-1-mediated inhibition. This heterogeneity may direct ICB efficacy on CD4+ T cells in HIV infection.

scholarly journals The Eδ enhancer controls the generation of CD4−CD8− αβTCR-expressing T cells that can give rise to different lineages of αβ T cells

2006 ◽  
Vol 203 (6) ◽  
pp. 1543-1550 ◽  
Author(s):  
Iannis Aifantis ◽  
Craig H. Bassing ◽  
Annette I. Garbe ◽  
Katie Sawai ◽  
Frederick W. Alt ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Receptor ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Cd8 Cells ◽  
Early Expression ◽  
Enhancer Function ◽  
Efficient Expansion ◽  
Deficient Mice

It is well established that the pre–T cell receptor for antigen (TCR) is responsible for efficient expansion and differentiation of thymocytes with productive TCRβ rearrangements. However, Ptcra- as well as Tcra-targeting experiments have suggested that the early expression of Tcra in CD4−CD8− cells can partially rescue the development of αβ CD4+CD8+ cells in Ptcra-deficient mice. In this study, we show that the TCR Eδ but not Eα enhancer function is required for the cell surface expression of αβTCR on immature CD4−CD8− T cell precursors, which play a crucial role in promoting αβ T cell development in the absence of pre-TCR. Thus, αβTCR expression by CD4−CD8− thymocytes not only represents a transgenic artifact but occurs under physiological conditions.

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