scholarly journals Blocking GARP-mediated activation of TGF-β1 did not alter innate or adaptive immune responses to bacterial infection or protein immunization in mice

2022 ◽  
Author(s):  
Mélanie Gaignage ◽  
Xuhao Zhang ◽  
Julie Stockis ◽  
Olivier Dedobbeleer ◽  
Camille Michiels ◽  
...  
Keyword(s):  
B Cells ◽  
Immune Responses ◽  
Bacterial Infection ◽  
B Cell ◽  
Tumor Immunity ◽  
Transmembrane Protein ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Protein Immunization ◽  
Tgf Β1

Abstract Transmembrane protein GARP binds latent TGF-β1 to form GARP:(latent)TGF-β1 complexes on the surface of several cell types including Tregs, B-cells, and platelets. Upon stimulation, these cells release active TGF-β1. Blocking TGF-β1 activation by Tregs with anti-GARP:TGF-β1 mAbs overcomes resistance to PD1/PD-L1 blockade and induces immune-mediated regressions of murine tumors, indicating that Treg-derived TGF-β1 inhibits anti-tumor immunity. TGF-β1 exerts a vast array of effects on immune responses. For example, it favors differentiation of TH17 cells and B-cell switch to IgA production, two important processes for mucosal immunity. Here, we sought to determine whether treatment with anti-GARP:TGF-β1 mAbs would perturb immune responses to intestinal bacterial infection. We observed no aggravation of intestinal disease, no systemic dissemination, and no alteration of innate or adaptative immune responses upon oral gavage of C. rodentium in highly susceptible Il22r−/− mice treated with anti-GARP:TGF-β1 mAbs. To examine the effects of GARP:TGF-β1 blockade on Ig production, we compared B cell- and TH cell- responses to OVA or CTB protein immunization in mice carrying deletions of Garp in Tregs, B cells, or platelets. No alteration of adaptive immune responses to protein immunization was observed in the absence of GARP on any of these cells. Altogether, we show that antibody-mediated blockade of GARP:TGF-β1 or genetic deletion of Garp in Tregs, B cells or platelets, do not alter innate or adaptive immune responses to intestinal bacterial infection or protein immunization in mice. Anti-GARP:TGF-β1 mAbs, currently tested for cancer immunotherapy, may thus restore anti-tumor immunity without severely impairing other immune defenses. Précis Immunotherapy with GARP:TGF-β1 mAbs may restore anti-tumor immunity without impairing immune or inflammatory responses required to maintain homeostasis or host defense against infection, notably at mucosal barriers.

scholarly journals The immunoreceptor adapter protein DAP12 suppresses B lymphocyte–driven adaptive immune responses

2011 ◽  
Vol 208 (8) ◽  
pp. 1661-1671 ◽  
Author(s):  
Takako Nakano-Yokomizo ◽  
Satoko Tahara-Hanaoka ◽  
Chigusa Nakahashi-Oda ◽  
Tsukasa Nabekura ◽  
Nadia K. Tchao ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Immune Responses ◽  
B Cell ◽  
Genetic Disorder ◽  
Elevated Serum ◽  
Sh2 Domain ◽  
Adapter Protein ◽  
Adaptive Immune Responses ◽  
Adaptive Immune

DAP12, an immunoreceptor tyrosine-based activation motif–bearing adapter protein, is involved in innate immunity mediated by natural killer cells and myeloid cells. We show that DAP12-deficient mouse B cells and B cells from a patient with Nasu-Hakola disease, a recessive genetic disorder resulting from loss of DAP12, showed enhanced proliferation after stimulation with anti-IgM or CpG. Myeloid-associated immunoglobulin-like receptor (MAIR) II (Cd300d) is a DAP12-associated immune receptor. Like DAP12-deficient B cells, MAIR-II–deficient B cells were hyperresponsive. Expression of a chimeric receptor composed of the MAIR-II extracellular domain directly coupled to DAP12 into the DAP12-deficient or MAIR-II–deficient B cells suppressed B cell receptor (BCR)–mediated proliferation. The chimeric MAIR-II–DAP12 receptor recruited the SH2 domain–containing protein tyrosine phosphatase 1 (SHP-1) after BCR stimulation. DAP12-deficient mice showed elevated serum antibodies against self-antigens and enhanced humoral immune responses against T cell–dependent and T cell–independent antigens. Thus, DAP12-coupled MAIR-II negatively regulates B cell–mediated adaptive immune responses.

scholarly journals B cells in chronic obstructive pulmonary disease: moving to center stage

2016 ◽  
Vol 311 (4) ◽  
pp. L687-L695 ◽  
Author(s):  
Francesca Polverino ◽  
Leen J. M. Seys ◽  
Ken R. Bracke ◽  
Caroline A. Owen
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
B Cells ◽  
Immune Responses ◽  
B Cell ◽  
Chronic Obstructive ◽  
Adaptive Immune Responses ◽  
Obstructive Pulmonary Disease ◽  
Lymphoid Follicles ◽  
Adaptive Immune ◽  
Copd Patients

Chronic inflammatory responses in the lungs contribute to the development and progression of chronic obstructive pulmonary disease (COPD). Although research studies focused initially on the contributions of the innate immune system to the pathogenesis of COPD, more recent studies have implicated adaptive immune responses in COPD. In particular, studies have demonstrated increases in B cell counts and increases in the number and size of B cell-rich lymphoid follicles in COPD lungs that correlate directly with COPD severity. There are also increases in lung levels of mediators that promote B cell maturation, activation, and survival in COPD patients. B cell products such as autoantibodies directed against lung cells, components of cells, and extracellular matrix proteins are also present in COPD lungs. These autoantibodies may contribute to lung inflammation and injury in COPD patients, in part, by forming immune complexes that activate complement components. Studies of B cell-deficient mice and human COPD patients have linked B cells most strongly to the emphysema phenotype. However, B cells have protective activities during acute exacerbations of COPD by promoting adaptive immune responses that contribute to host defense against pathogens. This review outlines the evidence that links B cells and B cell-rich lymphoid follicles to the pathogenesis of COPD and the mechanisms involved. It also reviews the potential and limitations of B cells as therapeutic targets to slow the progression of human COPD.

scholarly journals Mansonella perstans microfilaremic individuals are characterized by enhanced type 2 helper T and regulatory T and B cell subsets and dampened systemic innate and adaptive immune responses

2018 ◽  
Vol 12 (1) ◽  
pp. e0006184 ◽  
Author(s):  
Manuel Ritter ◽  
Winston Patrick Chounna Ndongmo ◽  
Abdel Jelil Njouendou ◽  
Nora Nganyewo Nghochuzie ◽  
Lucy Cho Nchang ◽  
...  
Keyword(s):  
Immune Responses ◽  
B Cell ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Mansonella Perstans ◽  
B Cell Subsets

The microRNA miR-29 controls innate and adaptive immune responses to intracellular bacterial infection by targeting interferon-γ

2011 ◽  
Vol 12 (9) ◽  
pp. 861-869 ◽  
Author(s):  
Feng Ma ◽  
Sheng Xu ◽  
Xingguang Liu ◽  
Qian Zhang ◽  
Xiongfei Xu ◽  
...  
Keyword(s):  
Immune Responses ◽  
Bacterial Infection ◽  
Interferon Γ ◽  
Adaptive Immune Responses ◽  
Adaptive Immune

scholarly journals B-1a B Cells that Link the Innate and Adaptive Immune Responses Are Lacking in the Absence of the Spleen

2002 ◽  
Vol 195 (6) ◽  
pp. 771-780 ◽  
Author(s):  
Hedda Wardemann ◽  
Thomas Boehm ◽  
Neil Dear ◽  
Rita Carsetti
Keyword(s):  
B Cells ◽  
Immune Responses ◽  
B Cell ◽  
Innate Immune ◽  
Streptococcal Infections ◽  
Wild Type ◽  
Adaptive Immune ◽  
Encapsulated Bacteria ◽  
Increased Susceptibility

Splenectomized individuals are prone to overwhelming infections with encapsulated bacteria and splenectomy of mice increases susceptibility to streptococcal infections, yet the exact mechanism by which the spleen protects against such infections is unknown. Using congenitally asplenic mice as a model, we show that the spleen is essential for the generation of B-1a cells, a B cell population that cooperates with the innate immune system to control early bacterial and viral growth. Splenectomy of wild-type mice further demonstrated that the spleen is also important for the survival of B-1a cells. Transfer experiments demonstrate that lack of these cells, as opposed to the absence of the spleen per se, is associated with an inability to mount a rapid immune response against streptococcal polysaccharides. Thus, absence of the spleen and the associated increased susceptibility to streptococcal infections is correlated with lack of B-1a B cells. These findings reveal a hitherto unknown role of the spleen in generating and maintaining the B-1a B cell pool.

CD154:CD40 Co-Stimulatory Blockade: A Novel Approach To Prevent Sensitization to Donor Alloantigens.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1273-1273
Author(s):  
Hong Xu ◽  
Jun Yan ◽  
Suzanne T. Ildstad
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
B Cell ◽  
Germinal Center ◽  
Cell Activation ◽  
Cell Tolerance ◽  
B Cell Activation ◽  
B Cell Tolerance ◽  
Adaptive Immune Responses ◽  
Adaptive Immune

Abstract Introduction: Recipient sensitization is one of the most critical problems facing clinical transplantation. Allosensitized recipients often rapidly reject vascularized solid organ grafts as a result of preformed anti-donor antibody. Similarly, bone marrow transplantation for sickle cell disease and thalassemia is limited by sensitization from transfusion. A method to prevent sensitization would have a significant impact on transplant outcomes. Until recently, T cells were believed to be the primary effector cell in the induction of adaptive immune responses. We recently found that humoral immunity provides a dominant barrier in allosensitization to MHC antigens. B cell activation occurs through T-cell-dependent responses via signaling from the co-stimulatory molecule CD154 (on T cells) to its ligand CD40 (on B cells). Here, we examined whether blocking the costimulatory interaction between T and B cells during exposure to alloantigen would prevent allosensitization. Materials and Methods: Mice deficient for CD154 molecule (CD154−/ −, H-2b), α β-TCR+ T cells (TCRβ −/ −, H-2b); or wild type B6 (H-2b) mice received allogeneic BALB/c (H-2d) skin grafts (SG) on day 0. Some B6 mice were also treated with anti-CD154 (day0 and day+3) and/or anti-α β-TCR mAb (day-3) peritransplant. Antibodies were detected by flow cytometry cross-match (FCM) assay and reported as mean fluorescence intensity (MFI). Results: CD154−/ − mice rejected primary BALB/c SG with a time course similar to normal B6 controls (12.4 ± 2.1 vs. 12.7 ± 2.4 days). TCRβ −/ − mice accepted SG permanently (>120 days). Notably, anti-donor antibody was not generated in either the CD154−/ − or TCRβ −/ − mice (MFI: 4.1 ± 0.1 and 4.2 ± 0.4) after SG compared with Ab in naïve serum (3.0±0.2). Sensitized B6 mice had significantly higher antibody titers (106.8 ± 35.1) 4 weeks after SG rejection. A second SG transplanted 5 to 7 weeks after the first graft was rejected at an accelerated rate (9.0 ± 0.8 days, P < 0.05) in the CD154−/ − mice, but no anti-donor MHC antibody was produced. Second grafts placed on TCRβ −/ − mice were accepted, as were the primary SG. In normal B6 recipients pretreated with anti-CD154 or anti-α β-TCR alone, SG survival was not significantly prolonged. The Ab titers were only slightly higher in mice treated with anti-CD154 (5.9±3.4; P>0.05) than in naïve mice, and significantly higher in mice treated with mAb anti-α β-TCR (45.1±25.6; P=0.03). The combined treatment with both mAbs resulted in complete abrogation of Ab production (4.2±0.9) and 70% of skin grafts survived >100 days. Germinal center formation, reflective of B cell activation, was completely disrupted in mice treated with anti-CD154 alone or combined with anti-α β-TCR. Conclusion: These results suggest that the CD40/CD154 co-stimulatory pathway is critically important in B cell activation to generate alloantibody. Notably, blocking molecular interactions between CD40/CD154 abrogated the generation of antibody and blocked germinal center formation, inducing B cell tolerance. The additional removal of recipient T cells in the context of co-stimulatory blockade resulted in the induction of T as well as B cell tolerance. These findings are the first demonstration that sensitization can be prevented through blockade of co-stimulatory interactions in the generation of adaptive immune responses and could have a significant impact on management of sensitized recipients in the clinic.

scholarly journals B Cell Immunosenescence

2020 ◽  
Vol 36 (1) ◽  
pp. 551-574 ◽  
Author(s):  
Daniela Frasca ◽  
Alain Diaz ◽  
Maria Romero ◽  
Denisse Garcia ◽  
Bonnie B. Blomberg
Keyword(s):  
Immune Responses ◽  
B Cell ◽  
Immune Cells ◽  
Cell Function ◽  
Current Knowledge ◽  
The Elderly ◽  
Low Grade ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
B Cell Function

Innate and adaptive immune responses decline with age, leading to greater susceptibility to infectious diseases and reduced responses to vaccines. Diseases are more severe in old than in young individuals and have a greater impact on health outcomes such as morbidity, disability, and mortality. Aging is characterized by increased low-grade chronic inflammation, so-called inflammaging, that represents a link between changes in immune cells and a number of diseases and syndromes typical of old age. In this review we summarize current knowledge on age-associated changes in immune cells with special emphasis on B cells, which are more inflammatory and less responsive to infections and vaccines in the elderly. We highlight recent findings on factors and pathways contributing to inflammaging and how these lead to dysfunctional immune responses. We summarize recent published studies showing that adipose tissue, which increases in size with aging, contributes to inflammaging and dysregulated B cell function.

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