scholarly journals Compromised Ox40 Function in Cd28-Deficient Mice Is Linked with Failure to Develop Cxc Chemokine Receptor 5–Positive Cd4 Cells and Germinal Centers

1999 ◽  
Vol 190 (8) ◽  
pp. 1115-1122 ◽  
Author(s):  
Lucy S.K. Walker ◽  
Adam Gulbranson-Judge ◽  
Sarah Flynn ◽  
Thomas Brocker ◽  
Chandra Raykundalia ◽  
...  
Keyword(s):  
T Cells ◽  
Fusion Protein ◽  
Chemokine Receptor ◽  
Germinal Center ◽  
Cd4 T Cells ◽  
Germinal Centers ◽  
Interleukin 4 ◽  
Cxc Chemokine ◽  
Germinal Center Formation

Mice rendered deficient in CD28 signaling by the soluble competitor, cytotoxic T lymphocyte–associated molecule 4–immunoglobulin G1 fusion protein (CTLA4-Ig), fail to upregulate OX40 expression in vivo or form germinal centers after immunization. This is associated with impaired interleukin 4 production and a lack of CXC chemokine receptor (CXCR)5 on CD4 T cells, a chemokine receptor linked with migration into B follicles. Germinal center formation is restored in CTLA4-Ig transgenic mice by coinjection of an agonistic monoclonal antibody to CD28, but this is substantially inhibited if OX40 interactions are interrupted by simultaneous injection of an OX40-Ig fusion protein. These data suggest that CD28-dependent OX40 ligation of CD4 T cells at the time of priming is linked with upregulation of CXCR5 expression, and migration of T cells into B cell areas to support germinal center formation.

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.

VavP-Bcl2 transgenic mice develop follicular lymphoma preceded by germinal center hyperplasia

Blood ◽  
2004 ◽  
Vol 103 (6) ◽  
pp. 2276-2283 ◽  
Author(s):  
Alexander Egle ◽  
Alan W. Harris ◽  
Mary L. Bath ◽  
Lorraine O'Reilly ◽  
Suzanne Cory
Keyword(s):  
T Cells ◽  
Transgenic Mice ◽  
Follicular Lymphoma ◽  
Germinal Center ◽  
Cd4 T Cells ◽  
Chromosome Translocation ◽  
Regulatory Sequences ◽  
Germinal Center Hyperplasia ◽  
B Lymphoid

Abstract In human follicular lymphoma the t(14; 18) chromosome translocation activates the antiapoptotic oncogene Bcl2 by linking it to the immunoglobulin heavy chain (IGH) locus. Transgenic mice expressing Bcl2 controlled by an Igh enhancer (Eμ) do not develop follicular lymphoma, although they do have an increased incidence of other B-lymphoid neoplasms. We have now analyzed tumorigenesis in mice bearing a Bcl2 transgene controlled by Vav gene regulatory sequences (VavP), which confer expression in multiple hematopoietic lineages. Unlike Eμ-Bcl2 mice, many VavP-Bcl2 mice older than 10 months developed follicular lymphoma. Young VavP-Bcl2 mice had an overabundance of enlarged germinal centers and greatly elevated numbers of cycling B cells that had undergone IgH class switching and V-gene hypermutation. The peripheral T-cell compartment was larger in the VavP-Bcl2 mice than in Eμ-Bcl2 strains and, notably, CD4 T cells were 5-fold increased over normal. The germinal center hyperplasia required CD4 T cells, because it could be abolished by anti-CD4 antibody in vivo. VavP-Bcl2 mice also had a propensity to develop kidney disease of the autoimmune type. We suggest that the increased survival capacity of B and T cells fosters prolonged germinal center reactions, and that autoreactivity and hypermutation conspire to generate follicular lymphoma.

scholarly journals The CXC Chemokine Receptor 3 Inhibits Autoimmune Cholangitis via CD8+ T Cells but Promotes Colitis via CD4+ T Cells

2018 ◽  
Vol 9 ◽  
Author(s):  
Qing-Zhi Liu ◽  
Wen-Tao Ma ◽  
Jing-Bo Yang ◽  
Zhi-Bin Zhao ◽  
Kai Yan ◽  
...  
Keyword(s):  
T Cells ◽  
Chemokine Receptor ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Autoimmune Cholangitis ◽  
Cxc Chemokine

scholarly journals gp39-CD40 interactions are essential for germinal center formation and the development of B cell memory.

1994 ◽  
Vol 180 (1) ◽  
pp. 157-163 ◽  
Author(s):  
T M Foy ◽  
J D Laman ◽  
J A Ledbetter ◽  
A Aruffo ◽  
E Claassen ◽  
...  
Keyword(s):  
B Cell ◽  
Germinal Center ◽  
Germinal Centers ◽  
Antibody Responses ◽  
Cell Memory ◽  
Specific Memory ◽  
B Cell Memory ◽  
Germinal Center Formation

gp39, the ligand for CD40 expressed on activated CD4+ T helper cells, is required for the generation of antibody responses to T-dependent (TD) antigens. Treatment of mice with anti-gp39 in vivo inhibits both primary and secondary antibody formation to TD, but not T-independent antigens. However, the role of this receptor-ligand pair in the development of germinal centers and the generation of B cell memory is as yet undefined. Using an antibody to gp39, this study examines the in vivo requirement for gp39-CD40 interactions in the induction of germinal center formation, as well as in the generation of B cell memory. Animals were immunized, treated in vivo with anti-gp39, and evaluated using immunohistochemical staining for the presence of splenic germinal centers 9-11 d after immunization. The results demonstrate that the formation of germinal centers was completely inhibited as a result of treatment with anti-gp39. Moreover, adoptive transfer experiments demonstrate that the generation of antigen-specific memory B cells is also inhibited as a consequence of blocking gp39-CD40 interactions. Taken together, the data demonstrate that gp39-CD40 interactions are critical not only for the generation of antibody responses, but also in the development of B cell memory.

scholarly journals Donor‐specific memory CD4 T cells provide help for alloantibody production in the absence of CD40/CD154 interactions and germinal center formation

2008 ◽  
Vol 22 (S1) ◽  
Author(s):  
Marion Rabant ◽  
Victoria Gorbacheva ◽  
Qi‐Wei Zhang ◽  
Mark Kolkin ◽  
Anna Valujskikh
Keyword(s):  
T Cells ◽  
Germinal Center ◽  
Cd4 T Cells ◽  
Specific Memory ◽  
Memory Cd4 T Cells ◽  
Germinal Center Formation

scholarly journals Interleukin 4–Producing Cd4 T Cells Arise from Different Precursors Depending on the Conditions of Antigen Exposure in Vivo

2000 ◽  
Vol 191 (4) ◽  
pp. 683-694 ◽  
Author(s):  
Gilles Foucras ◽  
Laurent Gapin ◽  
Christiane Coureau ◽  
Jean M. Kanellopoulos ◽  
Jean-Charles Guéry
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Interleukin 4 ◽  
Th2 Cells ◽  
Mouse Strains ◽  
Soluble Antigen ◽  
Th2 Response ◽  
Continuous Administration ◽  
Exposure In Vivo

The precursor origin of T helper (Th) cell subsets in vivo has been difficult to study and remains poorly investigated. We have previously shown that chronic administration of soluble protein antigen induces selective development of antigen-specific CD4 Th2 cells in genetically predisposed mouse strains. To analyze the origin of effector T cells in this model, we designed a competitive polymerase chain reaction–based approach to track public BV-J rearrangement expressed by CD4 T cells specific for hen egg white lysozyme (HEL) in BALB/c mice. We show that public T cell clones are predominantly associated with type 1 or 2 effector Th cells recovered after primary immunization in complete or incomplete Freund's adjuvant, respectively. Conversely, continuous administration of soluble antigen, which induces strong memory Th2 response, is associated with a dose-dependent reduction of public clone size by a mechanism resembling clonal anergy. Thus, soluble HEL–induced Th2 cells do not express the public complementarity determining region 3 motifs characteristic of immunogenic challenge in the presence of adjuvant. These results demonstrate that there are multiple pathways of induction of Th2 responses depending on the condition of antigen exposure in vivo, i.e., clonal immune deviation versus recruitment of a different pool of precursor cells.

scholarly journals Germinal Centers without T Cells

2000 ◽  
Vol 191 (3) ◽  
pp. 485-494 ◽  
Author(s):  
Carola García de Vinuesa ◽  
Matthew C. Cook ◽  
Jennifer Ball ◽  
Marion Drew ◽  
Yvonne Sunners ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
High Efficiency ◽  
Germinal Centers ◽  
Affinity Maturation ◽  
High Affinity ◽  
Safe Mechanism ◽  
Germinal Center Formation

Germinal centers are critical for affinity maturation of antibody (Ab) responses. This process allows the production of high-efficiency neutralizing Ab that protects against virus infection and bacterial exotoxins. In germinal centers, responding B cells selectively mutate the genes that encode their receptors for antigen. This process can change Ab affinity and specificity. The mutated cells that produce high-affinity Ab are selected to become Ab-forming or memory B cells, whereas cells that have lost affinity or acquired autoreactivity are eliminated. Normally, T cells are critical for germinal center formation and subsequent B cell selection. Both processes involve engagement of CD40 on B cells by T cells. This report describes how high-affinity B cells can be induced to form large germinal centers in response to (4-hydroxy-3-nitrophenyl) acetyl (NP)-Ficoll in the absence of T cells or signaling through CD40 or CD28. This requires extensive cross-linking of the B cell receptors, and a frequency of antigen-specific B cells of at least 1 in 1,000. These germinal centers abort dramatically at the time when mutated high-affinity B cells are normally selected by T cells. Thus, there is a fail-safe mechanism against autoreactivity, even in the event of thymus-independent germinal center formation.

scholarly journals Allergen immunotherapy decreases interleukin 4 production in CD4+ T cells from allergic individuals.

1993 ◽  
Vol 178 (6) ◽  
pp. 2123-2130 ◽  
Author(s):  
H Secrist ◽  
C J Chelen ◽  
Y Wen ◽  
J D Marshall ◽  
D T Umetsu
Keyword(s):  
T Cells ◽  
Allergic Rhinitis ◽  
Cd4 T Cells ◽  
Allergen Immunotherapy ◽  
Subcutaneous Administration ◽  
Interleukin 4 ◽  
Clinical Effects ◽  
Cytokine Profiles ◽  
Memory Cd4 T Cells

Allergen specific CD4+ T cell clones generated from allergic individuals have been shown to produce increased levels of the cytokine interleukin 4 (IL-4), compared to allergen specific clones generated from nonallergic individuals. This difference between CD4+ T cells from allergic and nonallergic individuals with regard to cytokine production in response to allergen is thought to be responsible for the development of allergic disease with increased IgE synthesis in atopic individuals. We examined the production of IL-4 in subjects with allergic rhinitis and in allergic individuals treated with allergen immunotherapy, a treatment which involves the subcutaneous administration of increasing doses of allergen and which is highly effective and beneficial for individuals with severe allergic rhinitis. We demonstrated that the quantity of IL-4 produced by allergen specific memory CD4+ T cells from allergic individuals could be considerably reduced by in vivo treatment with allergen (allergen immunotherapy). Immunotherapy reduced IL-4 production by allergen specific CD4+ T cells to levels observed with T cells from nonallergic subjects, or to levels induced with nonallergic antigens such as tetanus toxoid. In most cases the levels of IL-4 produced were inversely related to the length of time on immunotherapy. These observations indicate that immunotherapy accomplishes its clinical effects by reducing IL-4 synthesis in allergen specific CD4+ T cells. In addition, these observations indicate that the cytokine profiles of memory CD4+ T cells can indeed be altered by in vivo therapies. Thus, the cytokine profiles of memory CD4+ T cells are mutable, and are not fixed as had been suggested by studies of murine CD4+ memory T cells. Finally, treatment of allergic diseases with allergen immunotherapy may be a model for other diseases which may require therapies that alter inappropriate cytokine profiles of memory CD4+ T cells.

scholarly journals Engagement of CD28 Modulates CXC Chemokine Receptor 4 Surface Expression in Both Resting and CD3-Stimulated CD4+T Cells

2000 ◽  
Vol 164 (8) ◽  
pp. 4018-4024 ◽  
Author(s):  
Paola Secchiero ◽  
Davide Zella ◽  
Sabrina Curreli ◽  
Prisco Mirandola ◽  
Silvano Capitani ◽  
...  
Keyword(s):  
T Cells ◽  
Chemokine Receptor ◽  
Cd4 T Cells ◽  
Surface Expression ◽  
Cxc Chemokine Receptor 4 ◽  
Cxc Chemokine ◽  
Chemokine Receptor 4
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