Lymph node B lymphocyte trafficking is constrained by anatomy and highly dependent upon chemoattractant desensitization

Abstract B lymphocyte recirculation through lymph nodes (LNs) requires crossing endothelial barriers and chemoattractant-triggered cell migration. Here we show how LN anatomy and chemoattractant receptor signaling organize B lymphocyte LN trafficking. Blood-borne B cells predominately used CCR7 signaling to adhere to high endothelial venules (HEVs). New B cell emigrants slowly transited the HEV perivenule space, and thereafter localized nearby, avoiding the follicle. Eventually, the newly arrived B cells entered the basal portion of the follicle gradually populating it. In contrast, newly arriving activated B cells rapidly crossed HEVs and migrated toward the lymph node follicle. During their LN residency, recirculating B cells reacquired their sphingosine-1 phospate receptor 1 (S1P1) receptors and markedly attenuated their sensitivity to chemokines. Eventually, the B cells exited the LN follicle by entering the cortical lymphatics or returning to the paracortical cords. Upon entering the lymph, the B cells lost their polarity, down-regulated their S1P1 receptors, and subsequently strongly up-regulated their sensitivity to chemokines. These results are summarized in a model of homeostatic trafficking of B cells through LNs.

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Stepwise transmigration cascade of T and B cells through the perivascular channel in lymph node high endothelial venules

10.1101/2020.12.20.423079 ◽

2020 ◽

Author(s):

Kibaek Choe ◽

Jieun Moon ◽

Soo Yun Lee ◽

Eunjoo Song ◽

Ju Hee Back ◽

...

Keyword(s):

Cell Migration ◽

T Cell ◽

B Cells ◽

Lymph Nodes ◽

B Cell ◽

Hot Spots ◽

Dependent Manner ◽

T And B Cells ◽

High Endothelial Venules ◽

T Cell Migration

AbstractHigh endothelial venules (HEVs) effectively recruit circulating lymphocytes from the blood to lymph nodes. HEVs have endothelial cells (ECs) and perivascular sheaths consisting of fibroblastic reticular cells (FRCs). Many studies have characterized the multiple steps of lymphocyte migration interacting with ECs at the luminal side of HEVs. However, post-luminal migration steps are not well elucidated. Herein, we performed intravital imaging to investigate post-luminal T and B cell migration, consisting of trans-EC migration, crawling in the perivascular channel (a narrow space between ECs and FRCs) and trans-FRC migration. The post-luminal migration of T cells occurred in a PNAd-dependent manner. Remarkably, we found hot spots for the trans-EC and trans-FRC migration of T and B cells. Interestingly, T and B cells preferentially shared trans-FRC migration hot spots but not trans-EC migration hot spots. Furthermore, the trans-FRC T cell migration was confined to fewer sites than trans-EC T cell migration, and trans-FRC migration of T and B cells preferentially occurred at FRCs covered by CD11c+ dendritic cells in HEVs. These results suggest that HEV ECs and FRCs with perivascular DCs delicately regulate T and B cell entry into lymph nodes.

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Stepwise transmigration of T- and B cells through a perivascular channel in high endothelial venules

Life Science Alliance ◽

10.26508/lsa.202101086 ◽

2021 ◽

Vol 4 (8) ◽

pp. e202101086

Author(s):

Kibaek Choe ◽

Jieun Moon ◽

Soo Yun Lee ◽

Eunjoo Song ◽

Ju Hee Back ◽

...

Keyword(s):

Cell Migration ◽

T Cell ◽

B Cells ◽

Lymph Nodes ◽

B Cell ◽

Hot Spots ◽

Dependent Manner ◽

T And B Cells ◽

High Endothelial Venules ◽

T Cell Migration

High endothelial venules (HEVs) effectively recruit circulating lymphocytes from the blood to lymph nodes. HEVs have endothelial cells (ECs) and perivascular sheaths consisting of fibroblastic reticular cells (FRCs). Yet, post-luminal lymphocyte migration steps are not well elucidated. Herein, we performed intravital imaging to investigate post-luminal T- and B-cell migration in popliteal lymph node, consisting of trans-EC migration, crawling in the perivascular channel (a narrow space between ECs and FRCs) and trans-FRC migration. The post-luminal migration of T cells occurred in a PNAd-dependent manner. Remarkably, we found hot spots for the trans-EC and trans-FRC migration of T- and B cells. Interestingly, T- and B cells preferentially shared trans-FRC migration hot spots but not trans-EC migration hot spots. Furthermore, the trans-FRC T-cell migration was confined to fewer sites than trans-EC T-cell migration, and trans-FRC migration of T- and B cells preferentially occurred at FRCs covered by CD11c+ dendritic cells in HEVs. These results suggest that HEV ECs and FRCs with perivascular DCs delicately regulate T- and B-cell entry into peripheral lymph nodes.

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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 ◽

10.1182/blood-2004-05-1986 ◽

2004 ◽

Vol 104 (13) ◽

pp. 4104-4112 ◽

Cited By ~ 40

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)

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Induction of proliferation and blast transformation by interferon in human malignant and non-malignant lymph node B cells

Blood ◽

10.1182/blood.v73.8.2171.2171 ◽

1989 ◽

Vol 73 (8) ◽

pp. 2171-2181 ◽

Cited By ~ 9

Author(s):

L Ostlund ◽

P Biberfeld ◽

KH Robert ◽

B Christensson ◽

S Einhorn

Keyword(s):

Lymph Node ◽

B Cells ◽

Lymph Nodes ◽

B Cell ◽

Blood Cells ◽

Blast Transformation ◽

B Cell Lymphomas ◽

Lymph Node Cells ◽

Malignant Lymph Nodes ◽

In Cells

Abstract The influence of interferon (IFN) on cellular proliferation, blast transformation, and differentiation was studied in lymph node cells from 17 patients with B-cell lymphomas, one patient with T-cell lymphoma, and eight patients with enlarged, non-malignant lymph nodes. The effects of IFN on lymph node cells were compared with effects on mononuclear blood cells from chronic lymphocytic leukemia (CLL) patients and healthy donors. Natural IFN-alpha (nIFN-alpha) induced a proliferative response in cells from seven of 17 of the B-cell lymphomas, in two of eight of the non-malignant lymph nodes, and in lymphoid blood cells from two of 32 CLL patients. With few exceptions, the proliferating cells were B cells and the data suggest that IFN acts directly on the B cells. Proliferation was not induced with IFN in cells from the T-cell lymphoma or in mononuclear blood cells from 13 healthy donors. nIFN-alpha induced blast transformation in cells from ten of 14 of the B-cell lymphomas and in four of seven of the non- malignant lymph nodes. Also beta- and gamma-IFN were shown to induce proliferation and blast transformation in lymph node cells from some patients. No major effect on the expression of various differentiation markers could be observed following culture in the presence of nIFN- alpha. We conclude that IFNs can induce proliferation and blast transformation in malignant and non-malignant B cells from lymph nodes.

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Talin1 is required for integrin-dependent B lymphocyte homing to lymph nodes and the bone marrow but not for follicular B-cell maturation in the spleen

Blood ◽

10.1182/blood-2010-06-293506 ◽

2010 ◽

Vol 116 (26) ◽

pp. 5907-5918 ◽

Cited By ~ 24

Author(s):

Eugenia Manevich-Mendelson ◽

Valentin Grabovsky ◽

Sara W. Feigelson ◽

Guy Cinamon ◽

Yael Gore ◽

...

Keyword(s):

Bone Marrow ◽

B Cells ◽

Lymph Nodes ◽

B Cell ◽

B Lymphocyte ◽

Ex Vivo ◽

Cell Maturation ◽

White Pulp ◽

Marginal Zone B Cells ◽

B Cell Maturation

Abstract Talin1 is a key integrin coactivator. We investigated the roles of this cytoskeletal adaptor and its target integrins in B-cell lymphogenesis, differentiation, migration, and function. Using CD19 Cre-mediated depletion of talin1 selectively in B cells, we found that talin1 was not required for B-cell generation in the bone marrow or for the entry of immature B cells to the white pulp of the spleen. Loss of talin1 also did not affect B-cell maturation into follicular B cells but compromised differentiation of marginal zone B cells. Nevertheless, serum IgM and IgG levels remained normal. Ex vivo analysis of talin1-deficient spleen B cells indicated a necessary role for talin1 in LFA-1 and VLA-4 activation stimulated by canonical agonists, but not in B-cell chemotaxis. Consequently, talin1 null B splenocytes could not enter lymph nodes nor return to the bone marrow. Talin1 deficiency in B cells was also impaired in the humoral response to a T cell-dependent antigen. Collectively, these results indicate that talin1 is not required for follicular B-cell maturation in the spleen or homeostatic humoral immunity but is critical for integrin-dependent B lymphocyte emigration to lymph nodes and optimal immunity against T-dependent antigens.

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Systemic Tropheryma whippleii Infection Associated With Monoclonal B-Cell Proliferation: A Helicobacter pylori–Type Pathogenesis?

Archives of Pathology & Laboratory Medicine ◽

10.5858/2003-127-1619-stwiaw ◽

2003 ◽

Vol 127 (12) ◽

pp. 1619-1622

Author(s):

Sa Wang ◽

Linda M. Ernst ◽

Brian R. Smith ◽

Giovanni Tallini ◽

John G. Howe ◽

...

Keyword(s):

Polymerase Chain Reaction ◽

Cell Proliferation ◽

Lymph Node ◽

B Cells ◽

Lymph Nodes ◽

B Cell ◽

Chain Reaction ◽

Mesenteric Lymph ◽

Whipple Disease ◽

Polymerase Chain

Abstract We report a case of Whipple disease in a 55-year-old woman who presented with arthralgia, weight loss, and lymphadenopathy. Tropheryma whippleii bacilli were identified in the mesenteric lymph nodes by diastase-resistant periodic acid–Schiff stain and confirmed by electron microscopy. Retrospectively, previous biopsy specimens from the duodenum and right axillary lymph node of this patient, which were initially considered to demonstrate reactive changes, also showed features consistent with involvement by Whipple disease. At the time of presentation, a large κ-restricted monoclonal B-cell population with the phenotype CD20+CD19+CD5−CD10− was identified in the patient's peripheral blood, lymph nodes, and bone marrow by flow cytometry study. The monoclonality of the mesenteric lymph node B cells was confirmed by immunohistochemical stain for κ chain after antigen retrieval and also by polymerase chain reaction with the primer set targeting FR2-VH. Routine cytogenetic study failed to reveal any chromosomal abnormalities, and polymerase chain reaction for Bcl-2 major and minor breakpoint cluster of t(14:18) was not detected. The monoclonal B cells have persisted in blood for the entire follow-up period (10 months). The possibility of reactive monoclonal B-cell proliferation versus Whipple disease–related B-cell lymphoma is discussed.

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MyD88- and TRIF-Independent Induction of Type I Interferon Drives Naive B Cell Accumulation but Not Loss of Lymph Node Architecture in Lyme Disease

Infection and Immunity ◽

10.1128/iai.00969-13 ◽

2014 ◽

Vol 82 (4) ◽

pp. 1548-1558 ◽

Cited By ~ 19

Author(s):

Christine J. Hastey ◽

Jennine Ochoa ◽

Kimberley J. Olsen ◽

Stephen W. Barthold ◽

Nicole Baumgarth

Keyword(s):

Lymph Node ◽

B Cells ◽

Lyme Disease ◽

Lymph Nodes ◽

B Cell ◽

Time Course ◽

Type I Interferon ◽

Type I ◽

Content Type ◽

Specific Immunity

ABSTRACTRapidly after infection, liveBorrelia burgdorferi, the causative agent of Lyme disease, is found within lymph nodes, causing rapid and strong tissue enlargement, a loss of demarcation between B cell follicles and T cell zones, and an unusually large accumulation of B cells. We sought to explore the mechanisms underlying these changes, as lymph tissue disruption could be detrimental for the development of robustBorrelia-specific immunity. A time course study demonstrated that the loss of the normal lymph node structure was a distinct process that preceded the strong increases in B cells at the site. The selective increases in B cell frequencies were due not to proliferation but rather to cytokine-mediated repositioning of B cells to the lymph nodes, as shown with various gene-targeted and bone marrow irradiation chimeras. These studies demonstrated thatB. burgdorferiinfection induced type I interferon receptor (IFNR) signaling in lymph nodes in a MyD88- and TRIF-independent manner and that type I IFNR indirect signaling was required for the excessive increases of naive B cells at those sites. It did not, however, drive the observed histopathological changes, which occurred independently also from major shifts in the lymphocyte-homing chemokines, CXCL12, CXCL13, and CCL19/21, as shown by quantitative reverse transcription-PCR (qRT-PCR), flow cytometry, and transwell migration experiments. Thus,B. burgdorferiinfection drives the production of type I IFN in lymph nodes and in so doing strongly alters the cellular composition of the lymph nodes, with potential detrimental effects for the development of robustBorrelia-specific immunity.

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Trafficking of adoptively transferred B lymphocytes in B-lymphocyte-deficient mice.

Journal of Experimental Biology ◽

10.1242/jeb.200.14.2057 ◽

1997 ◽

Vol 200 (14) ◽

pp. 2057-2062

Author(s):

R Roth ◽

M J Mamula

Keyword(s):

Lymph Node ◽

B Cells ◽

B Cell ◽

B Lymphocyte ◽

Lymphoid Organs ◽

Axillary Lymph ◽

Cell Transfer ◽

Cellular Interactions ◽

Cell Distribution ◽

Deficient Mice

Many studies have investigated the fate of adoptively transferred lymphocytes in recipient mice, although little is known of the sites where these transferred cells reside at particular time points. Using flow cytometry, we analyzed the trafficking pattern of adoptively transferred naive B cells into the lymphoid organs of syngeneic B-cell-deficient (microMT) mice. Within the first 24 h of transfer, the location of B cells was highly dependent on the mode of B-cell transfer. When B cells were injected subcutaneously into microMT mice, they showed a different trafficking pattern from cells administered into the peritoneal cavity or injected intravenously. After subcutaneous transfer into the thigh, the greatest number of B cells was detected in the popliteal lymph node nearest to the injection site, whereas the lowest number was detected in the axillary lymph node opposite to the injection side. Within the first 24 h of either intraperitoneal and intravenous injection, B cells were found in approximately equal numbers in the lymph nodes and the spleen. Two days later, the B-cell distribution in the lymphoid organs appeared to be independent of the mode of B-cell transfer. A transient decrease in the numbers of splenic and lymph node B cells occurred 9 days after B-cell transfer (a decrease from 70 to 87%) prior to the outgrowth of B cells that occurs 21 days after transfer. These studies are useful for understanding the numbers of B cells that may be required in adoptive transfer studies and their potential cellular interactions at particular physiological sites based on the route of cell transfer.

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Myo1e modulates the recruitment of B cells to inguinal lymph nodes

10.1101/668608 ◽

2019 ◽

Author(s):

Daniel Alberto Girón-Pérez ◽

Eduardo Vadillo ◽

Michael Schnoor ◽

Leopoldo Santos-Argumedo

Keyword(s):

Cell Migration ◽

B Cells ◽

Lymph Nodes ◽

Signaling Pathway ◽

High Endothelial Venules ◽

Long Tail ◽

Summary Statement ◽

And Migration

AbstractThe recruitment of leukocyte to high endothelium venules and their migration to the lymph nodes are critical steps to initiate an immune response. Cell migration is regulated by the actin cytoskeleton where myosins have a very import role. Myo1e is a long tail class I myosin highly expressed in B cells that not have been studied in the context of cell migration. By using an in vivo model, through the use of intravital microscopy, we demonstrated the relevance of Myo1e in the adhesion and the migration of B cells in high endothelial venules. These observations were confirmed by in vitro experiments. We also registered a reduction in the expression of integrins and F-actin in the protrusion of B lymphocytes membrane. Deficiencies in vesicular trafficking can explain the decrease of integrins on the surface. Interestingly, Myo1e is associated with focal adhesion kinase (FAK). The lack of Myo1e affected the phosphorylation of FAK and AKT, and the activity of RAC-1, disturbing the FAK/PI3K/RAC-1 signaling pathway. Together, our results indicate critical participation of Myo1e in the mechanism of B cell migration.Summary statementMyo1e participate in the adhesion and migration in the high endothelial venules by regulation of integrins and the PI3K/FAK/RAC-1 signaling pathway.

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Induction of proliferation and blast transformation by interferon in human malignant and non-malignant lymph node B cells

Blood ◽

10.1182/blood.v73.8.2171.bloodjournal7382171 ◽

1989 ◽

Vol 73 (8) ◽

pp. 2171-2181

Author(s):

L Ostlund ◽

P Biberfeld ◽

KH Robert ◽

B Christensson ◽

S Einhorn

Keyword(s):

Lymph Node ◽

B Cells ◽

Lymph Nodes ◽

B Cell ◽

Blood Cells ◽

Blast Transformation ◽

B Cell Lymphomas ◽

Lymph Node Cells ◽

Malignant Lymph Nodes ◽

In Cells

The influence of interferon (IFN) on cellular proliferation, blast transformation, and differentiation was studied in lymph node cells from 17 patients with B-cell lymphomas, one patient with T-cell lymphoma, and eight patients with enlarged, non-malignant lymph nodes. The effects of IFN on lymph node cells were compared with effects on mononuclear blood cells from chronic lymphocytic leukemia (CLL) patients and healthy donors. Natural IFN-alpha (nIFN-alpha) induced a proliferative response in cells from seven of 17 of the B-cell lymphomas, in two of eight of the non-malignant lymph nodes, and in lymphoid blood cells from two of 32 CLL patients. With few exceptions, the proliferating cells were B cells and the data suggest that IFN acts directly on the B cells. Proliferation was not induced with IFN in cells from the T-cell lymphoma or in mononuclear blood cells from 13 healthy donors. nIFN-alpha induced blast transformation in cells from ten of 14 of the B-cell lymphomas and in four of seven of the non- malignant lymph nodes. Also beta- and gamma-IFN were shown to induce proliferation and blast transformation in lymph node cells from some patients. No major effect on the expression of various differentiation markers could be observed following culture in the presence of nIFN- alpha. We conclude that IFNs can induce proliferation and blast transformation in malignant and non-malignant B cells from lymph nodes.

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