Journal Article10.1002/EJI.1830240118
Induction of B cell costimulatory function by recombinant murine CD40 ligand.
Mary K. Kennedy,Kendall M. Mohler,Kurt D. Shanebeck,Peter Robert Baum,Kathleen S. Picha,Carol Otten-Evans,Charles A. Janeway,Kenneth H. Grabstein +7 more
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TL;DR: It is shown that recombinant membrane‐bound murine CD40L induces B cells to express costimulatory function for the proliferation of CD4+ Tcells and suggested that CD40 L‐activated B cells express an additional costimulation activity that is not associated with LPS‐ activated B cells.
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Abstract: T cell-dependent regulation of B cell growth and differentiation involves an interaction between CD40, a B cell surface molecule, and the CD40 ligand (CD40L) which is expressed on activated CD4+ T cells. In the current study, we show that recombinant membrane-bound murine CD40L induces B cells to express costimulatory function for the proliferation of CD4+ T cells. CD40L- or lipopolysaccharide (LPS)-activated, but not control-cultured B cells were strong costimulators of anti-CD3 or alloantigen-dependent T cell responses. The molecular interactions responsible for the increased costimulatory functions were examined by analyzing the activated B cells for changes in the expression of two costimulatory molecules, B7 and heat-stable antigen (HSA), as well as by the use of antagonists of B7 and HSA (CTLA4.Fc and 20C9, respectively). The expression of both B7 and HSA was enhanced on B cells activated with LPS. As observed in previous studies, the costimulatory activity of the LPS-activated B cells was dependent on both B7 and HSA and was completely inhibited in the presence of a combination of CTLA4.Fc and 20C9. In contrast, activation of B cells with CD40L induced the expression of B7 but did not enhance the expression of HSA. In addition the costimulatory activity of the CD40L-activated B cells was partially, but not completely, inhibited by the combination of CTLA4.Fc and 20C9. These results demonstrate that CD40L regulates costimulatory function of B cells in part by inducing the expression of B7 and suggest that CD40L-activated B cells express an additional costimulatory activity that is not associated with LPS-activated B cells.
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Citations
Application of new therapies in Graves' disease and thyroid-associated ophthalmopathy: animal models and translation to human clinical trials.
TL;DR: The recent development of an induced model of experimental Graves' disease, although incomplete as it lacks the extrathyroidal manifestations, provided opportunities to investigate immune intervention strategies, including influence upon the autoreactive B and T cell players in the autoimmune process.
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Immune regulation by B cells and antibodies: A view towards the clinic
Kai Hoehlig,Vicky Lampropoulou,Toralf Roch,Patricia Neves,Elisabeth Calderon-Gomez,Stephen M. Anderton,Ulrich Steinhoff,Simon Fillatreau +7 more
TL;DR: Clinical examples illustrating the potential of antibodies as treatment for immune-mediated disorders and the underlying mechanisms are analyzed to examine the regulatory functions of activated B cells, their involvement in the termination of some experimental autoimmune diseases, and their use in cell-based therapy for such pathologies.
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Differential Regulation of Soluble and Membrane CD40L Proteins in T Cells: Implication of ADAM-10
Gertsch Matthies,Kelli Michelle +1 more
- 01 Jan 2006
Abstract: CD40 ligand is an important immunoregulatory protein expressed by T cells. This protein exists as two isoforms, a membrane glycoprotein and a truncated soluble form. Here we demonstrate that membrane and soluble CD40L (sCD40L) are differentially regulated depending upon the activation stimulus. In T cell receptor activated cells, both membrane and sCD40L proteins are expressed and CD28 costimulation further increases their expression. The dissection of TCR generated signals into calcium and PKC-dependent pathways demonstrates that calcium is sufficient to induce membrane CD40L yet insufficient for sCD40L. In contrast, sCD40L is preferentially induced by PKC. Moreover, sCD40L production is blocked by Zn(2+)-dependent metalloproteinase inhibitors while membrane CD40L is concurrently increased. This profile suggests the potential involvement of the ADAM-10 protease which was subsequently shown to cleave membrane CD40L to generate sCD40L. Given the role of sCD40L in numerous disease pathologies and its ability to activate proximal and distal immune responses, the regulated cleavage of CD40L may likely contribute to disease mechanisms.
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Antibody to gp39, the ligand for CD40 significantly inhibits the humoral response from Graves' thyroid tissues xenografted into severe combined immunodeficient (SCID) mice.
Erika Resetkova,Keisuke Kawai,Tetsuya Enomoto,Guillermo Arreaza,Rachel A. Togun,Teresa M. Foy,Randolph J. Noelle,Robert Volpé +7 more
TL;DR: In spite of a profound immunosuppressive effect on the humoral response by directly blocking CD40-gp39 interactions in vivo, this did not result in complete deletion of the responding Th in the thyroid specimens.
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The disease progression in the keratin 14 IL-4-transgenic mouse model of atopic dermatitis parallels the up-regulation of B cell activation molecules, proliferation and surface and serum IgE.
TL;DR: The data suggest that activated B cells may play a role in atopic dermatitis disease development by up‐regulating serum IgE concentration, which serves as a marker of disease onset.
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Peter S. Linsley,William E. Brady,Mark Urnes,Laura Sue Grosmaire,Nitin K. Damle,Jeffrey A. Ledbetter +5 more
TL;DR: These findings provide direct evidence that, like its structural homologue CD28, CTLA- 4 is able to bind the B7 counter-receptor on activated B cells.
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Peter S. Linsley,William E. Brady,Laura Sue Grosmaire,Alejandro Aruffo,Nitin K. Damle,Jeffrey A. Ledbetter +5 more
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Richard J. Armitage,William C. Fanslow,Laura Strockbine,Timothy A. Sato,Ky N. Clifford,Brian M. Macduff,Dirk M. Anderson,Steven D. Gimpel,Terri Davis-Smith,Charles R. Maliszewski,Edward A. Clark,Craig A. Smith,Kenneth H. Grabstein,David Cosman,Melanie K. Spriggs +14 more
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