scholarly journals Arrested B Lymphopoiesis and Persistence of Activated B Cells in Adult Interleukin 7−/− Mice

2001 ◽  
Vol 194 (8) ◽  
pp. 1141-1150 ◽  
Author(s):  
Thiago L. Carvalho ◽  
Tomaz Mota-Santos ◽  
Ana Cumano ◽  
Jocelyne Demengeot ◽  
Paulo Vieira
Keyword(s):  
T Cell ◽  
B Lymphocytes ◽  
Early Life ◽  
B Lymphocyte ◽  
Marginal Zone ◽  
Adult Life ◽  
Fold Increase ◽  
B Lymphopoiesis ◽  
Interleukin 7 ◽  
B1 Cells

Interleukin 7 is a crucial factor for the development of murine T and B lymphocytes. We now report that, in the absence of interleukin 7, B lymphocyte production takes place exclusively during fetal and perinatal life, ceasing after 7 wk of age. In peripheral organs, however, the pool of B lymphocytes is stable throughout adult life and consists only of cells that belong to the B1 and marginal zone (MZ) compartments. This is accompanied by a 50-fold increase in the frequency of immunoglobulin (Ig)M- and IgG-secreting cells, and the concentration of serum immunoglobulins is increased three- to fivefold. Both the MZ phenotype and the increase in serum IgM are T cell independent. These findings reveal a previously undescribed pathway of B lymphopoiesis that is active in early life and is interleukin 7 independent. This pathway generates B1 cells and a normal sized MZ B lymphocyte compartment.

scholarly journals Replication history of B lymphocytes reveals homeostatic proliferation and extensive antigen-induced B cell expansion

2007 ◽  
Vol 204 (3) ◽  
pp. 645-655 ◽  
Author(s):  
Menno C. van Zelm ◽  
Tomasz Szczepański ◽  
Mirjam van der Burg ◽  
Jacques J.M. van Dongen
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
B Cell ◽  
B Lymphocytes ◽  
Cell Expansion ◽  
B Lymphocyte ◽  
Somatic Hypermutation ◽  
Homeostatic Proliferation ◽  
History Of ◽  
Lymphocyte Homeostasis

The contribution of proliferation to B lymphocyte homeostasis and antigen responses is largely unknown. We quantified the replication history of mouse and human B lymphocyte subsets by calculating the ratio between genomic coding joints and signal joints on kappa-deleting recombination excision circles (KREC) of the IGK-deleting rearrangement. This approach was validated with in vitro proliferation studies. We demonstrate that naive mature B lymphocytes, but not transitional B lymphocytes, undergo in vivo homeostatic proliferation in the absence of somatic mutations in the periphery. T cell–dependent B cell proliferation was substantially higher and showed higher frequencies of somatic hypermutation than T cell–independent responses, fitting with the robustness and high affinity of T cell–dependent antibody responses. More extensive proliferation and somatic hypermutation in antigen-experienced B lymphocytes from human adults compared to children indicated consecutive responses upon additional antigen exposures. Our combined observations unravel the contribution of proliferation to both B lymphocyte homeostasis and antigen-induced B cell expansion. We propose an important role for both processes in humoral immunity. These new insights will support the understanding of peripheral B cell regeneration after hematopoietic stem cell transplantation or B cell–directed antibody therapy, and the identification of defects in homeostatic or antigen-induced B cell proliferation in patients with common variable immunodeficiency or another antibody deficiency.

Whole-Exome Sequencing Links CARD11 Inactivation with SCID

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 258-258
Author(s):  
Johann Greil ◽  
Tobias Rausch ◽  
Thomas Giese ◽  
Obul Reddy Bandapalli ◽  
Volker Daniel ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
T Lymphocytes ◽  
Exome Sequencing ◽  
B Lymphocytes ◽  
Whole Exome Sequencing ◽  
B Lymphocyte ◽  
Whole Exome ◽  
Life Threatening

Abstract Abstract 258 Primary immunodeficiencies represent model diseases for the mechanistic understanding of the human innate and the adaptive immune response and are per se clinically highly relevant, because in SCID patients infections by opportunistic pathogens are typically life-threatening early in life. We identified an infant of consanguineous parents suffering from a novel form of SCID, who presented with a life-threatening Pneumocystis jirovecii pneumonia. This entity was characterized by agammaglobulinemia and profoundly deficient T-cell function despite quantitatively normal T- and B-lymphocytes. Lymphocyte proliferation was strongly inhibited after stimulation of PBMCs with T-cell mitogens such as PHA, Con A, or anti-CD3 monoclonal antibody. The expression of several T-cell response associated cytokines upon stimulation with PMA/ionomycin was dramatically reduced in comparison to normal controls. By contrast, proliferation induced by the classical B-cell mitogen PWM was almost comparable to healthy controls. Immunophenotyping revealed a predominantly naïve phenotype (CD45RA+ CCR7+) in CD4+ and CD8+ T-lymphocytes, whereas central memory T-lymphocytes (CD45RA− CCR7+) were nearly absent. B-lymphocytes from peripheral blood were mainly naïve B-cells (CD27−) with a uniformly immature transitional B-lymphocyte phenotype (CD24++, CD38++). Patient B-lymphocytes retained the ability to proliferate and differentiate in response to BCR-independent stimuli, while their response to BCR activation was defective. Our findings thus revealed a combined defect of TCR-mediated T-lymphocyte functions and BCR-mediated B-lymphocyte functions but did not enable us to link the immunological phenotype with one of the known molecularly defined categories of SCID. Diagnostic whole-exome sequencing and systematic variant categorization revealed a single pathogenic homozygous nonsense mutation of the caspase recruitment domain 11 (CARD11) gene. CARD11 is a scaffold protein that is known to be required for the assembly and activation of the NF-kB complex. In reconstitution assays we demonstrated that the patient derived truncated CARD11 protein is defective in antigen receptor signaling and NF-kB activation. Several lines of evidence substantiate the involvement of the identified CARD11 mutation in the new form of SCID that we report here. First, PCR and Sanger re-sequencing validated the truncating CARD11 mutation to be homozygous in the patient and heterozygous in the parents, in agreement with the recessive transmission of the mutation through the healthy consanguineous parents. Second, CARD11 is a scaffold protein required for TCR- and BCR-induced NF-kB activation as well as lymphocyte activation and proliferation, which is specifically expressed in hematopoietic cells, consistent with a causative role of CARD11 mutations in the context of an immune disorder. Third, the GUK domain of CARD11, which is missing in the mutated form of CARD11 due to truncation, was previously reported to be necessary for NF-kB activation by PMA/ionomycin treatment, further supporting the presumed damaging nature of the homozygous CARD11 mutation observed in the female patient reported here. Finally, the immunological findings in this patient are compatible with the phenotype of a previously described Card11 −/− k.o. mouse, which shows a selective defect in NF-κB activation leading to diminished antigen receptor or PKC mediated proliferation and defective cytokine production in T-cells and B-cells. Thus, we have identified an inactivating CARD11 mutation linking defective NF-kB signaling with a novel cause of autosomal recessive SCID, which must be considered in the diagnostic assessment of patients with suspected SCID but with quantitatively normal T-cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals CELL INTERACTIONS BETWEEN HISTOINCOMPATIBLE T AND B LYMPHOCYTES

1973 ◽  
Vol 137 (6) ◽  
pp. 1405-1418 ◽  
Author(s):  
David H. Katz ◽  
Toshiyuki Hamaoka ◽  
Baruj Benacerraf
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
B Lymphocytes ◽  
B Lymphocyte ◽  
Cell Interaction ◽  
Antibody Responses ◽  
T And B Lymphocytes ◽  
Cooperative Interactions

Several experimental approaches, designed specifically to circumvent the possible contribution of a complicating "allogeneic effect," have been successfully used to answer the question of physiologic cooperative interactions between histoincompatible T and B lymphocytes in antibody responses to hapten-protein conjugates. This was accomplished for in vivo cell transfer studies by using an F1 hybrid host as the recipient of irradiated, carrier-primed T lymphocytes from one parent and 2,4-dinitrophenyl (DNP)-primed B lymphocytes from the opposite strain. Under these conditions, very good T-B cell cooperative interactions were observed to occur between T and B lymphocyte populations derived from syngeneic donors, whereas no cooperative response was obtained when T cells were derived from one parental strain and B cells from the other. Corroborative experiments were performed in a totally in vitro system in which DNP-primed B cells developed good secondary anti-DNP antibody responses in vitro to soluble DNP-keyhole limpet hemocyanin (KLH) when cultured in the presence of irradiated KLH-primed T cells derived from syngenic donors but not from allogeneic donors. The failure of histoincompatible T and B lymphocytes to effect physiologic cooperative interactions has important implications for our understanding of how such interactions normally occur. The possibility that these results reflect the existence of a "block" of some sort to cell-cell interaction by virtue of the presence of a foreign major histocompatibility antigen on the surface of either cell has been definitively ruled out in the present studies. These observations demonstrate that the gene(s) that conditions the capability for physiologic T-B cell cooperation must be shared in common by the respective cell types, and suggest, furthermore, that this gene (or genes) belongs to the major histocompatibility system of the mouse. These findings, together with other relevant phenomena described previously, have led us to postulate that there exists on the B lymphocyte surface an "acceptor" molecule either for the putative active T cell product or for the T cell itself. The important genetic considerations and the possible sequence of events surrounding the actual T-B cell interaction implied by these postulates are discussed in detail.

Low marginal zone-like B lymphocytes and natural antibodies characterize skewed B-lymphocyte subpopulations in del22q11 DiGeorge patients

2015 ◽  
Vol 161 (2) ◽  
pp. 144-149 ◽  
Author(s):  
Adam Klocperk ◽  
Ester Mejstříková ◽  
Jana Kayserová ◽  
Tomáš Kalina ◽  
Anna Šedivá
Keyword(s):  
B Lymphocytes ◽  
B Lymphocyte ◽  
Marginal Zone ◽  
Lymphocyte Subpopulations ◽  
Natural Antibodies

scholarly journals A small CD11b+ human B1 cell subpopulation stimulates T cells and is expanded in lupus

2011 ◽  
Vol 208 (13) ◽  
pp. 2591-2598 ◽  
Author(s):  
Daniel O. Griffin ◽  
Thomas L. Rothstein
Keyword(s):  
T Cell ◽  
B Lymphocytes ◽  
Cell Population ◽  
Therapeutic Benefit ◽  
Cd4 T Cell ◽  
Cell Subpopulation ◽  
B Cell Depletion ◽  
Immunoglobulin Production ◽  
B1 Cells ◽  
Adult Peripheral Blood

A primary function of B lymphocytes is immunoglobulin production; however, the therapeutic benefit of B cell depletion in autoimmune diseases previously thought to be T cell mediated suggests that some B cells fulfill other roles in autoimmunity. We examined the recently identified human B1 cell population for T cell stimulatory activity. We found two kinds of B1 cells that are distinguished by multiple surface markers and distinct transcriptomic profiles. In both umbilical cord and adult peripheral blood, a CD11b+ subset constitutes ∼1 out of every 8–10 B1 cells, whereas a CD11b− subset constitutes the remaining B1 cells. These B1 cell populations differ functionally. CD11b− B1 cells spontaneously secrete much more IgM than CD11b+ B1 cells. In contrast, CD11b+ B1 cells express more CD86, and more efficiently stimulate allogeneic CD4+ T cell expansion, than CD11b− B1 cells. The frequency of these CD11b+ B1 cells is markedly elevated in lupus patients. CD11b+ B1 cells in lupus patients express more CD86 and have increased T cell–stimulating activity in disease. This work distinguishes a novel, T cell–interacting B1 cell population whose abundance and activity may be a reflection of, and a therapeutic target in, autoimmune disease.

scholarly journals The Rac2 Guanosine Triphosphatase Regulates B Lymphocyte Antigen Receptor Responses and Chemotaxis and Is Required for Establishment of B-1a and Marginal Zone B Lymphocytes

2002 ◽  
Vol 168 (7) ◽  
pp. 3376-3386 ◽  
Author(s):  
Ben A. Croker ◽  
David M. Tarlinton ◽  
Leonie A. Cluse ◽  
Alana J. Tuxen ◽  
Amanda Light ◽  
...  
Keyword(s):  
B Lymphocytes ◽  
B Lymphocyte ◽  
Marginal Zone ◽  
Antigen Receptor ◽  
Lymphocyte Antigen ◽  
Guanosine Triphosphatase

scholarly journals Rapidly induced, T-cell–independent xenoantibody production is mediated by marginal zone B cells and requires help from NK cells

Blood ◽  
2007 ◽  
Vol 110 (12) ◽  
pp. 3926-3935 ◽  
Author(s):  
Shengqiao Li ◽  
Yehong Yan ◽  
Yuan Lin ◽  
Dominique M. Bullens ◽  
Omer Rutgeerts ◽  
...  
Keyword(s):  
T Cell ◽  
Nk Cells ◽  
T Lymphocyte ◽  
B Lymphocyte ◽  
Marginal Zone ◽  
Nk Cell ◽  
Lymphocyte Subpopulations ◽  
Target Cells ◽  
Marginal Zone B Cells ◽  
Ifn Γ

AbstractXenoantibody production directed at a wide variety of T lymphocyte–dependent and T lymphocyte–independent xenoantigens remains the major immunologic obstacle for successful xenotransplantation. The B lymphocyte subpopulations and their helper factors, involved in T-cell–independent xenoantibody production are only partially understood, and their identification will contribute to the clinical applicability of xenotransplantation. Here we show, using models involving T-cell–deficient athymic recipient mice, that rapidly induced, T-cell–independent xenoantibody production is mediated by marginal zone B lymphocytes and requires help from natural killer (NK) cells. This collaboration neither required NK-cell–mediated IFN-γ production, nor NK-cell–mediated cytolytic killing of xenogeneic target cells. The T-cell–independent IgM xenoantibody response could be partially suppressed by CD40L blockade.

scholarly journals B lymphocyte precursors and myeloid progenitors survive in diffusion chamber cultures but B cell differentiation requires close association with stromal cells

Blood ◽  
1987 ◽  
Vol 70 (5) ◽  
pp. 1418-1424 ◽  
Author(s):  
PC Kierney ◽  
K Dorshkind
Keyword(s):  
B Lymphocytes ◽  
Stromal Cells ◽  
Direct Contact ◽  
Stromal Cell ◽  
B Lymphocyte ◽  
Cell Layer ◽  
Close Association ◽  
Culture Conditions ◽  
B Lymphopoiesis ◽  
Hemopoietic Cells

Abstract The aim of this study was to investigate the relative contribution of direct contact with stromal cells v stromal cell-derived soluble mediators to the differentiation of B lymphocytes and cells from other hematopoietic lineages. This was investigated by making a comparison between hemopoietic cells grown in direct contact with stroma to those in diffusion chambers (DCs) placed over purified populations of stroma. The source of stromal cells was adherent layers from myeloid or lymphoid long-term bone marrow cultures that had been treated with mycophenolic acid, an antibiotic that depletes hemopoietic cells from the cultures but retains a functional stroma. The cells seeded into the chambers were fresh marrow cells that had been passed through two consecutive nylon wool columns to deplete cell populations capable of forming an adherent cell layer in vitro. DCs were placed in wells in which the adherent stroma, growing under myeloid or lymphoid conditions, was present. The results indicate that progenitors of granulocytes and macrophages survived and differentiated in DCs under myeloid culture conditions, as the number of cells and absolute number of CFU-GM increased over that present in the reseed population. These levels, however, were markedly less than in parallel cultures in which the cells were seeded directly onto stroma. Hematopoiesis in DCs placed over hemopoietically active stroma was not optimal, suggesting that factors were used by those hemopoietic cells closest to the stroma. A B lymphocyte precursor survived in DCs under myeloid but not lymphoid conditions, and its differentiation into B lymphocytes was dependent on close association with stromal cells; B lymphopoiesis initiated when cells from DCs grown under myeloid conditions were harvested from the chambers and seeded directly onto stroma initiated and maintained under lymphoid bone marrow culture conditions. B lymphopoiesis did not initiate if the DC from the myeloid conditions was left intact and placed directly over a lymphoid stromal cell layer in lymphoid conditions.

scholarly journals B lymphocyte precursors and myeloid progenitors survive in diffusion chamber cultures but B cell differentiation requires close association with stromal cells

Blood ◽  
1987 ◽  
Vol 70 (5) ◽  
pp. 1418-1424
Author(s):  
PC Kierney ◽  
K Dorshkind
Keyword(s):  
B Lymphocytes ◽  
Stromal Cells ◽  
Direct Contact ◽  
Stromal Cell ◽  
B Lymphocyte ◽  
Cell Layer ◽  
Close Association ◽  
Culture Conditions ◽  
B Lymphopoiesis ◽  
Hemopoietic Cells

The aim of this study was to investigate the relative contribution of direct contact with stromal cells v stromal cell-derived soluble mediators to the differentiation of B lymphocytes and cells from other hematopoietic lineages. This was investigated by making a comparison between hemopoietic cells grown in direct contact with stroma to those in diffusion chambers (DCs) placed over purified populations of stroma. The source of stromal cells was adherent layers from myeloid or lymphoid long-term bone marrow cultures that had been treated with mycophenolic acid, an antibiotic that depletes hemopoietic cells from the cultures but retains a functional stroma. The cells seeded into the chambers were fresh marrow cells that had been passed through two consecutive nylon wool columns to deplete cell populations capable of forming an adherent cell layer in vitro. DCs were placed in wells in which the adherent stroma, growing under myeloid or lymphoid conditions, was present. The results indicate that progenitors of granulocytes and macrophages survived and differentiated in DCs under myeloid culture conditions, as the number of cells and absolute number of CFU-GM increased over that present in the reseed population. These levels, however, were markedly less than in parallel cultures in which the cells were seeded directly onto stroma. Hematopoiesis in DCs placed over hemopoietically active stroma was not optimal, suggesting that factors were used by those hemopoietic cells closest to the stroma. A B lymphocyte precursor survived in DCs under myeloid but not lymphoid conditions, and its differentiation into B lymphocytes was dependent on close association with stromal cells; B lymphopoiesis initiated when cells from DCs grown under myeloid conditions were harvested from the chambers and seeded directly onto stroma initiated and maintained under lymphoid bone marrow culture conditions. B lymphopoiesis did not initiate if the DC from the myeloid conditions was left intact and placed directly over a lymphoid stromal cell layer in lymphoid conditions.

Recombinant Human Interleukin-7 (CYT107) Enhances CD4 and CD8 T Cell Recovery Following T-Cell Depleted Allogeneic Hematopoietic Stem Cell Transplant In Patients with Myeloid Malignancies

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 674-674
Author(s):  
Miguel-Angel Perales ◽  
Jenna D. Goldberg ◽  
Leuren Lechner ◽  
Jianda Yuan ◽  
Esperanza Papadopoulos ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Fold Increase ◽  
Cell Transplant ◽  
Immune Recovery ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Interleukin 7 ◽  
T Cell Reconstitution

Abstract Abstract 674 Immune recovery is an important determinant in multiple outcomes following allogeneic hematopoietic stem cell transplant (allo-HSCT). Delays in B and T cell reconstitution are associated with an increased risk of infection, relapse and secondary malignancy. Strategies to enhance post-transplant T-cell reconstitution could therefore improve morbidity and mortality after allo-HSCT. The cytokine Interleukin-7 (IL-7) is a unique therapeutic candidate to promote immune reconstitution because it has a central role in T cell development and survival. Murine models of allo-HSCT have demonstrated that IL-7 can enhance thymopoiesis as well as promote peripheral T cell survival and expansion. Initial clinical trials performed with recombinant human IL-7 (rhIL-7) have demonstrated a dose-dependent expansion of CD4+ and CD8+ T cells with an acceptable toxicity profile in patients with solid tumors or HIV infection. Hence we are conducting a phase I trial of post-transplant administration of rhIL-7 (CYT107, Cytheris Inc) in recipients of a T cell depleted (TCD) allo-HSCT to determine the safety, toxicity and biological activity on T cell reconstitution. To date, 9 patients (AML=7, MDS=2), with a median age of 59.3 years (range 27–67 years) have been treated with escalating doses of rhIL-7 (3 at 10 mcg/kg, 6 at 20 mcg/kg) administered subcutaneously weekly for 3 weeks following TCD allo-HSCT from an HLA compatible donor. Accrual is ongoing in the final cohort (30 mcg/kg). Recombinant hIL-7 was started at a median of 96 days post allo-HSCT (range 61–244 days). Most patients experienced transient minor injection site reactions. One patient (20 mcg/kg) developed a biopsy proven hypersensitivity drug rash a week after the first injection and was removed from the study (evaluable for toxicity but not immune recovery endpoints). No other significant injection-related toxicities have occurred, and no patients have developed GVHD. No anti-IL-7 antibodies or neutralizing antibodies have developed following rhIL-7 injection. Two of 9 patients with high-risk AML have relapsed (4 and 9 months post rhIL-7), an incidence consistent with published data in patients undergoing allo-HSCT for AML in CR, irrespective of T-cell depletion. Eight patients remain alive with a median follow-up of 14.5 months post rhIL-7 administration. At baseline, the median T cell counts were 91/mm3 (range 5 – 219 /mm3), 43/mm3 (range 9 – 299 /mm3) and 0 (range 0 – 17 /mm3) for CD4+, CD8+ and CD45RA+ T cells, respectively. Preliminary assessment of the immunological effects of rhIL-7 in 8 evaluable patients has demonstrated an increase in CD4+ T cells exhibiting a naïve or central memory phenotype (69% median increase over baseline at day 21 – range 8% to 35-fold increase), and CD8+ T cells exhibiting a naïve or effector memory phenotype (94% median increase over baseline at day 28 – range 0 to 11-fold increase). There was no observed effect on the frequency of CD4+CD25+FoxP3+ T cells or CD19+ B cells. TCR excision circles (TREC) analysis performed on CD4+ and CD8+ subsets in the first 6 patients, using absolute quantification real-time PCR, demonstrated increases in TRECs in 5/6 patients indicating enhanced T cell production. Finally, all 3 CMV-seropositive patients developed CD8+ T cell CMV-specific responses detected by intracellular IFNγ production to overlapping CMV-pp65 pentadecapeptides peptide pools after administration of rhIL-7. In one patient, we also analyzed CMV-specific T-cell frequency using HLA-A*0201 restricted MHC-tetramers. The highest CMV-specific response levels were noted in this patient with a history of CMV viremia and low-level CMV-specific CD8+ T cells prior to rhIL-7 (5.3-fold increase to the A0201-restricted immunodominant NLV peptide by tetramer assay after rhIL-7). Our pre-clinical data and early clinical results suggest that administration of rhIL-7 in recipients of a TCD allo-HSCT has minimal toxicity and can enhance post-transplant immune recovery without causing GVHD. Disclosures: Perales: Cytheris: Research Funding. Croughs:Cytheris: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Morre:Cytheris: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. van den Brink:Cytheris: Research Funding.

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