scholarly journals In vivo function of the lipid raft protein Flotillin 1 during CD8+ T cell-mediated host surveillance

2018 ◽  
Author(s):  
Xenia Ficht ◽  
Nora Ruef ◽  
Bettina Stolp ◽  
Federica Moalli ◽  
Nicolas Page ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lipid Raft ◽  
Scaffolding Protein ◽  
Minor Role ◽  
Lymphoid Tissues ◽  
Two Photon Microscopy ◽  
T Cell Migration ◽  
And Migration

AbstractFlotillin-1 (Flot1) is a highly conserved, ubiquitously expressed lipid raft-associated scaffolding protein. Migration of Flot1-deficient neutrophils is impaired due to a decrease in myosin II-mediated contractility. Flot1 also accumulates in the uropod of polarized T cells, suggesting an analogous role in T cell migration. Here, we analyzed morphology and migration of naïve and memory WT and Flot1-/- CD8+ T cells in lymphoid and non-lymphoid tissues with intravital two-photon microscopy, as well as their clonal expansion during antiviral immune responses. Flot1-/- CD8+ T cells displayed minor alterations in cell shape and motility parameters in vivo but showed comparable homing to lymphoid organs and infiltration into non-lymphoid tissues. Taken together, Flot1 plays a detectable but unexpectedly minor role for CD8+ T cell behavior under physiological conditions.

scholarly journals Activation of Wnt5A signaling is required for CXC chemokine ligand 12–mediated T-cell migration

Blood ◽  
2009 ◽  
Vol 114 (7) ◽  
pp. 1366-1373 ◽  
Author(s):  
Manik C. Ghosh ◽  
Gary D. Collins ◽  
Bolormaa Vandanmagsar ◽  
Kalpesh Patel ◽  
Margaret Brill ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Migration ◽  
T Cell ◽  
Cxcr4 Signaling ◽  
T Cell Migration ◽  
Wnt5a Expression ◽  
Cxc Chemokine ◽  
Chemokine Ligand ◽  
And Migration

Abstract Chemokines mediate the signaling and migration of T cells, but little is known about the transcriptional events involved therein. Microarray analysis of CXC chemokine ligand (CXCL) 12−treated T cells revealed that Wnt ligands are significantly up-regulated during CXCL12 treatment. Real-time polymerase chain reaction and Western blot analysis confirmed that the expression of noncanonical Wnt pathway members (eg, Wnt5A) was specifically up-regulated during CXCL12 stimulation, whereas β-catenin and canonical Wnt family members were selectively down-regulated. Wnt5A augmented signaling through the CXCL12-CXCR4 axis via the activation of protein kinase C. Moreover, Wnt5A expression was required for CXCL12–mediated T-cell migration, and rWnt5A sensitized human T cells to CXCL12-induced migration. Furthermore, Wnt5A expression was also required for the sustained expression of CXCR4. These results were further supported in vivo using EL4 thymoma metastasis as a model of T-cell migration. Together, these data demonstrate that Wnt5A is a critical mediator of CXCL12-CXCR4 signaling and migration in human and murine T cells.

scholarly journals Lymph node topology dictates T cell migration behavior

2007 ◽  
Vol 204 (4) ◽  
pp. 771-780 ◽  
Author(s):  
Joost B. Beltman ◽  
Athanasius F.M. Marée ◽  
Jennifer N. Lynch ◽  
Mark J. Miller ◽  
Rob J. de Boer
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymphoid Tissues ◽  
Migration Behavior ◽  
Spatially Explicit Model ◽  
Two Photon Microscopy ◽  
Two Photon ◽  
T Cell Migration ◽  
Random Direction ◽  
Consistent Direction

Adaptive immunity is initiated by T cell recognition of foreign peptides presented on dendritic cells (DCs) by major histocompatibility molecules. These interactions take place in secondary lymphoid tissues, such as lymph nodes (LNs) and spleen, and hence the anatomical structure of these tissues plays a crucial role in the development of immune responses. Two-photon microscopy (2PM) imaging in LNs suggests that T cells walk in a consistent direction for several minutes, pause briefly with a regular period, and then take off in a new, random direction. Here, we construct a spatially explicit model of T cell and DC migration in LNs and show that all dynamical properties of T cells could be a consequence of the densely packed LN environment. By means of 2PM experiments, we confirm that the large velocity fluctuations of T cells are indeed environmentally determined rather than resulting from an intrinsic motility program. Our simulations further predict that T cells self-organize into microscopically small, highly dynamic streams. We present experimental evidence for the presence of such turbulent streams in LNs. Finally, the model allows us to estimate the scanning rates of DCs (2,000 different T cells per hour) and T cells (100 different DCs per hour).

Transgenic overexpression of the CC chemokine CCL21 disrupts T-cell migration

Blood ◽  
2001 ◽  
Vol 98 (13) ◽  
pp. 3562-3568 ◽  
Author(s):  
Kent W. Christopherson ◽  
James J. Campbell ◽  
Robert A. Hromas
Keyword(s):  
T Cells ◽  
T Cell ◽  
Large Family ◽  
Lymphoid Tissues ◽  
Cell Trafficking ◽  
Cc Chemokine ◽  
T Cell Migration ◽  
Cell Subpopulations ◽  
And Migration ◽  
T Cell Subpopulations

Abstract Chemokines are a large family of cytokines that direct normal leukocyte migration. They also have been implicated in leukocyte development and in the pathogenesis of many diseases. The CC chemokine CCL21, also known as Exodus-2, SLC, 6Ckine, and TCA4 induces both the adhesion and migration of human T cells. CCL21 is hypothesized to regulate the trafficking of T cells through secondary lymphoid tissues. To test this hypothesis, a transgenic mouse model was generated that placed the expression of mouse CCL21 (mCCL21) under the control of the T cell-specific lck promoter to abrogate the concentration gradient to which T cells normally respond. Overexpression of mCCL21 in T cells resulted in defects in CCL21- and CCL19-induced T-cell chemotaxis, node T-cell subpopulations, and lymph node architecture. The regulation of T-cell trafficking in secondary lymphoid tissues by CCL21 is therefore a tightly regulated system that can be altered by changes in the level of environmental CCL21 protein.

scholarly journals In Vivo–Activated Cd4 T Cells Upregulate Cxc Chemokine Receptor 5 and Reprogram Their Response to Lymphoid Chemokines

1999 ◽  
Vol 190 (8) ◽  
pp. 1123-1134 ◽  
Author(s):  
K. Mark Ansel ◽  
Louise J. McHeyzer-Williams ◽  
Vu N. Ngo ◽  
Michael G. McHeyzer-Williams ◽  
Jason G. Cyster
Keyword(s):  
T Cells ◽  
Cell Migration ◽  
T Cell ◽  
Chemokine Receptor ◽  
Cd4 T Cells ◽  
Lymphoid Tissue ◽  
Lymphoid Tissues ◽  
T Cell Migration ◽  
Cxc Chemokine

Migration of antigen-activated CD4 T cells to B cell areas of lymphoid tissues is important for mounting T cell–dependent antibody responses. Here we show that CXC chemokine receptor (CXCR)5, the receptor for B lymphocyte chemoattractant (BLC), is upregulated on antigen-specific CD4 T cells in vivo when animals are immunized under conditions that promote T cell migration to follicles. In situ hybridization of secondary follicles for BLC showed high expression in mantle zones and low expression in germinal centers. When tested directly ex vivo, CXCR5hi T cells exhibited a vigorous chemotactic response to BLC. At the same time, the CXCR5hi cells showed reduced responsiveness to the T zone chemokines, Epstein-Barr virus–induced molecule 1 (EBI-1) ligand chemokine (ELC) and secondary lymphoid tissue chemokine (SLC). After adoptive transfer, CXCR5hi CD4 T cells did not migrate to follicles, indicating that additional changes may occur after immunization that help direct T cells to follicles. To further explore whether T cells could acquire an intrinsic ability to migrate to follicles, CD4−CD8− double negative (DN) T cells from MRL-lpr mice were studied. These T cells normally accumulate within follicles of MRL-lpr mice. Upon transfer to wild-type recipients, DN T cells migrated to follicle proximal regions in all secondary lymphoid tissues. Taken together, our findings indicate that reprogramming of responsiveness to constitutively expressed lymphoid tissue chemokines plays an important role in T cell migration to the B cell compartment of lymphoid tissues.

scholarly journals Form and pattern of MUC1 expression on T cells activated in vivo or in vitro suggests a function in T-cell migration

Immunology ◽  
2003 ◽  
Vol 108 (1) ◽  
pp. 32-41 ◽  
Author(s):  
Isabel Correa ◽  
Tim Plunkett ◽  
Anda Vlad ◽  
Arron Mungul ◽  
Jessica Candelora-Kettel ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Migration ◽  
T Cell ◽  
Muc1 Expression ◽  
T Cell Migration

scholarly journals CCR7 ligands stimulate the intranodal motility of T lymphocytes in vivo

2007 ◽  
Vol 204 (3) ◽  
pp. 489-495 ◽  
Author(s):  
Tim Worbs ◽  
Thorsten R. Mempel ◽  
Jasmin Bölter ◽  
Ulrich H. von Andrian ◽  
Reinhold Förster
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Cd4 T Cells ◽  
Movement Behavior ◽  
Wild Type ◽  
Two Photon Microscopy ◽  
Two Photon ◽  
Systemic Application

In contrast to lymphocyte homing, little is known about molecular cues controlling the motility of lymphocytes within lymphoid organs. Applying intravital two-photon microscopy, we demonstrate that chemokine receptor CCR7 signaling enhances the intranodal motility of CD4+ T cells. Compared to wild-type (WT) cells, the average velocity and mean motility coefficient of adoptively transferred CCR7-deficient CD4+ T lymphocytes in T cell areas of WT recipients were reduced by 33 and 55%, respectively. Both parameters were comparably reduced for WT T lymphocytes migrating in T cell areas of plt/plt mice lacking CCR7 ligands. Importantly, systemic application of the CCR7 ligand CCL21 was sufficient to rescue the motility of WT T lymphocytes inside T cell areas of plt/plt recipients. Comparing the movement behavior of T cells in subcapsular areas that are devoid of detectable amounts of CCR7 ligands even in WT mice, we failed to reveal any differences between WT and plt/plt recipients. Furthermore, in both WT and plt/plt recipients, highly motile T cells rapidly accumulated in the subcapsular region after subcutaneous injection of the CCR7 ligand CCL19. Collectively, these data identify CCR7 and its ligands as important chemokinetic factors stimulating the basal motility of CD4+ T cells inside lymph nodes in vivo.

scholarly journals New differentiation pathway for double-negative regulatory T cells that regulates the magnitude of immune responses

Blood ◽  
2006 ◽  
Vol 109 (9) ◽  
pp. 4071-4079 ◽  
Author(s):  
Dong Zhang ◽  
Wei Yang ◽  
Nicolas Degauque ◽  
Yan Tian ◽  
Allison Mikita ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cell Surface ◽  
Immune Responses ◽  
Lymphoid Tissues ◽  
Double Negative ◽  
Healthy Humans

Abstract Recent studies have demonstrated that in peripheral lymphoid tissues of normal mice and healthy humans, 1% to 5% of αβ T-cell receptor–positive (TCR+) T cells are CD4−CD8− (double-negative [DN]) T cells, capable of down-regulating immune responses. However, the origin and developmental pathway of DN T cells is still not clear. In this study, by monitoring CD4 expression during T-cell proliferation and differentiation, we identified a new differentiation pathway for the conversion of CD4+ T cells to DN regulatory T cells. We showed that the converted DN T cells retained a stable phenotype after restimulation and that furthermore, the disappearance of cell-surface CD4 molecules on converted DN T cells was a result of CD4 gene silencing. The converted DN T cells were resistant to activation-induced cell death (AICD) and expressed a unique set of cell-surface markers and gene profiles. These cells were highly potent in suppressing alloimmune responses both in vitro and in vivo in an antigen-specific manner. Perforin was highly expressed by the converted DN regulatory T cells and played a role in DN T-cell–mediated suppression. Our findings thus identify a new differentiation pathway for DN regulatory T cells and uncover a new intrinsic homeostatic mechanism that regulates the magnitude of immune responses. This pathway provides a novel, cell-based, therapeutic approach for preventing allograft rejection.

scholarly journals A Detailed Analysis of Parameters Supporting the Engraftment and Growth of Chronic Lymphocytic Leukemia Cells in Immune-Deficient Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Piers E. M. Patten ◽  
Gerardo Ferrer ◽  
Shih-Shih Chen ◽  
Jonathan E. Kolitz ◽  
Kanti R. Rai ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Intraperitoneal Administration ◽  
Human Condition ◽  
Lymphocytic Leukemia ◽  
Lymphoid Tissues ◽  
Quiescent State

Patient-derived xenograft models of chronic lymphocytic leukemia (CLL) can be created using highly immunodeficient animals, allowing analysis of primary tumor cells in an in vivo setting. However, unlike many other tumors, CLL B lymphocytes do not reproducibly grow in xenografts without manipulation, proliferating only when there is concomitant expansion of T cells. Here we show that in vitro pre-activation of CLL-derived T lymphocytes allows for a reliable and robust system for primary CLL cell growth within a fully autologous system that uses small numbers of cells and does not require pre-conditioning. In this system, growth of normal T and leukemic B cells follows four distinct temporal phases, each with characteristic blood and tissue findings. Phase 1 constitutes a period during which resting CLL B cells predominate, with cells aggregating at perivascular areas most often in the spleen. In Phase 2, T cells expand and provide T-cell help to promote B-cell division and expansion. Growth of CLL B and T cells persists in Phase 3, although some leukemic B cells undergo differentiation to more mature B-lineage cells (plasmablasts and plasma cells). By Phase 4, CLL B cells are for the most part lost with only T cells remaining. The required B-T cell interactions are not dependent on other human hematopoietic cells nor on murine macrophages or follicular dendritic cells, which appear to be relatively excluded from the perivascular lymphoid aggregates. Notably, the growth kinetics and degree of anatomic localization of CLL B and T cells is significantly influenced by intravenous versus intraperitoneal administration. Importantly, B cells delivered intraperitoneally either remain within the peritoneal cavity in a quiescent state, despite the presence of dividing T cells, or migrate to lymphoid tissues where they actively divide; this dichotomy mimics the human condition in that cells in primary lymphoid tissues and the blood are predominately resting, whereas those in secondary lymphoid tissues proliferate. Finally, the utility of this approach is illustrated by documenting the effects of a bispecific antibody reactive with B and T cells. Collectively, this model represents a powerful tool to evaluate CLL biology and novel therapeutics in vivo.

scholarly journals Differential nanoscale organisation of LFA-1 modulates T cell migration

2019 ◽  
Author(s):  
Michael J. Shannon ◽  
Judith Pineau ◽  
Juliette Griffié ◽  
Jesse Aaron ◽  
Tamlyn Peel ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Single Molecule ◽  
Inflammatory Responses ◽  
Leading Edge ◽  
Negative Regulator ◽  
Signalling Molecules ◽  
T Cell Migration ◽  
Cell Velocity ◽  
And Migration

AbstractEffector T-cells rely on integrins to drive adhesion and migration to facilitate their immune function. Heterodimeric transmembrane integrin LFA-1 (αLβ2) regulates adhesion and migration through linkage of the extracellular matrix with the intracellular actin treadmill machinery. We quantitated the velocity and direction of F-actin flow in migrating T-cells alongside single molecule localisation of transmembrane and intracellular LFA-1. Our results show that retrograde actin flow positively correlated and immobile actin negatively correlated with T-cell velocity. Plasma membrane localised LFA-1 forms unique nano-clustering patterns in the leading edge, compared to the mid-focal zone, in migrating T-cells. Deleting the cytosolic phosphatase PTPN22, a negative regulator of integrin signaling, increased T-cell velocity, and leading-edge cluster co-localisation of pY397 FAK, pY416 Src family kinases and LFA-1. These data suggest that differential nanoclustering patterns of LFA-1 in migrating T-cells can instruct intracellular signalling linked with the actin treadmill. Our data presents a paradigm where T cells modulate the nanoscale organisation of adhesion and signalling molecules to fine tune their migration speed. This has implications for the regulation of immune and inflammatory responses.

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