Pierre Graber

T Lymphocytes Induce Endothelial Cell Matrix Metalloproteinase Expression by a CD40L-Dependent Mechanism : Implications for Tubule Formation

Neovascularization frequently accompanies chronic immune responses characterized by T cell infiltration and activation. Angiogenesis requires endothelial cells (ECs) to penetrate extracellular matrix, a process that involves matrix metalloproteinases (MMPs). We report here that activated human T cells mediate contact-dependent expression of MMPs in ECs through CD40/CD40 ligand signaling. Ligation of CD40 on ECs induced de novo expression of gelatinase B (MMP-9), increased interstitial collagenase (MMP-1) and stromelysin (MMP-3), and activated gelatinase A (MMP-2). Recombinant human CD40L induced expression of MMPs by human vascular ECs to a greater extent than did maximally effective concentrations of interleukin-1beta or tumor necrosis factor-alpha. Moreover, activation of human vascular ECs through CD40 induced tube formation in a three-dimensional fibrin matrix gel assay, an effect antagonized by a MMP inhibitor. These results demonstrated that activation of ECs by interaction with T cells induced synthesis and release of MMPs and promoted an angiogenic function of ECs via CD40L-CD40 signaling. As vascular cells at the sites of chronic inflammation, such as atherosclerotic plaques, express CD40 and its ligand, our findings suggest that ligation of CD40 on ECs can mediate aspects of vascular remodeling and neovessel formation during atherogenesis and other chronic immune reactions.

CD23 Regulates monocyte activation through a novel interaction with the adhesion molecules CD11b-CD18 and CD11c-CD18

CD23 is expressed on a variety of haemopoietic cells and displays pleiotropic activities in vitro. We report that in addition to CD21 and IgE, CD23 interacts specifically with the CD11b and CD11c, the alpha chains of the beta 2 integrin adhesion molecule complexes CD11b-CD18 and CD11c-CD18, on monocytes. Full-length recombinant CD23 incorporated into fluorescent liposomes was shown to bind to COS cells transfected with cDNA encoding either CD11b-CD18 or CD11c-CD18 but not with CD11a-CD18. The interaction was specifically inhibited by anti-CD11b or anti-CD11c, respectively, and by anti-CD23 MAbs. The functional significance of this ligand pairing was demonstrated by triggering CD11b and CD11c on monocytes with either recombinant CD23 or anti-CD11b and anti-CD11c MAbs to cause a marked increase in nitrite-oxidative products and pro-inflammatory cytokines (IL-1 beta, IL-6, and TNF alpha). These CD23-mediated activities were decreased by Fab fragments of MAbs to CD11b, CD11c, and CD23. These results demonstrate that CD11b and CD11c are receptors for CD23 and that this novel ligand pairing regulates important activities of monocytes.

The distribution of IL-13 receptor α1 expression on B cells, T cells and monocytes and its regulation by IL-13 and IL-4

To study the expression of IL‐13 receptor α1 (IL‐13Rα1), specific monoclonal antibodies (mAb) were generated. Surface expression of the IL‐13Rα1 on B cells, monocytes and T cells was assessed by flow cytometry using these specific mAb. Among tonsillar B cells, the expression was the highest on the IgD+ CD38− B cell subpopulation which is believed to represent naive B cells. Expression was also detectable on a large fraction of the IgD−CD38− B cells but not on CD38+ B cells. Activation under conditions which promote B cell Ig class switching up‐regulated the expression of the receptor. However, the same stimuli had an opposite effect for IL‐13Rα1 expression levels on monocytes. While IL‐13Rα1 mRNA was clearly detectable in T cell preparations, no surface expression was detected. However, permeabilization of the T cells showed a clear intracellular expression of the receptor. A soluble form of the receptor was immunoprecipitated from the supernatant of activated peripheral T cells, suggesting that T cell IL‐13Rα1 might have functions unrelated to the capacity to form a type II IL‐4 / IL‐13R with IL‐4Rα.

Structure and functions of CD23.

This review summarizes recent data on CD23, a low affinity receptor for IgE (Fc epsilon RII). CD23 is the only FcR which does not belong to the immunoglobulin gene superfamily. The CD23 molecule was discovered independently as an IgE receptor on human lymphoblastoid B cells [1], as a cell surface marker expressed on Epstein-Barr-Virus-transformed B cells (EBVCS) [2] and as a B-cell activation antigen (Blast 2) [3]. CD23 was shown to be a low affinity receptor for IgE [4,5]. Similar to most FcR, soluble forms of CD23 (sCD23) are released into extracellular fluids. The soluble fragments formed by proteolytic cleavage of surface CD23 are not only capable of binding IgE (IgE binding factors) but also exhibit multiple functions that are not IgE related. These observations together with the finding that CD23 displays significant homology with Ca(2+)-dependent (C-type) animal lectins, suggested the existence of natural ligands other than IgE. The recent finding that CD23 interacts with CD21, CD11b and CD11c indicates that CD23 should be viewed not only as a low affinity IgE receptor but also as an adhesion molecule involved in cell-cell interaction. After a brief overview of the molecular structure, there follows a discussion of the biological activities ascribed to human CD23.

CD23 and B-cell activation

The past year has seen the publication of significant new findings on the regulation of CD23 expression, the precise interaction of CD23 with CD21 and its functional consequences. Moreover, new advances have been made in unravelling the biochemical network of events downstream from the triggering of CD23 in human B cells. Analyses of the properties of CD23-deficient mice have demonstrated a link between IgE regulation and CD23 in vivo.

A new role for CD23 in inflammation

Abstract CD23, is expressed on a variety of haematopoietic cell types and displays pleiotropic activities in vitro . Here Jean-Yves Bonnefoy and collegues discuss a novel interaction between CD23 and the α chains of the β 2 integrins, CD11b and CD11c, that leads to a proinflammatory pattern of macrophage activation. They describe how neutralizing antibodies to CD23 can decrease the severity of murine arthritis.

Regulation of IgE Synthesis by CD23/CD21 Interaction

At least two cell-derived signals have been shown to be necessary for the induction of immunoglobulin isotype switching in B cells. The first signal is given by either of the soluble lymphokines interleukin (IL)-4 or IL-13 which induce germline epsilon transcript expression, but alone is insufficient to trigger secretion of IgE. The second signal is provided by a physical interaction between B cells and activated T cells, basophils and mast cells, and it has been shown that the CD40/CD40L pairing is crucial for mediating IgE synthesis. In HIGM1 syndrome, which is characterized by greatly decreased levels of IgG, IgA and IgE, there are mutations in CD40L resulting in a completely non-functional extracellular domain. CD40L is therefore playing a central role in Ig switching. Amongst the numerous pairs of surface adhesion molecules, the CD23/CD21 pair seems to play a key role in the generation of IgE. The CD23 molecule is positively and negatively regulated by factors which increase or decrease IgE production, respectively. Antibodies to CD23 have been shown to inhibit IL-4-induced human IgE production in vitro and to inhibit antigen-specific IgE responses in a rat model, in an isotype-selective manner. CD23 interacts with CD21 on B cells, preferentially driving IgE production. CD23 recognises two main epitopes on the CD21 molecule. One region consists of short consensus repeat sequences (SCRs) 1-2 and the other of SCRs 5-8. In the latter region ASn370 and Asn295 are critical in the interaction with the lectin CD23. Therefore, a restricted number of cytokines and surface molecules seems to selectively regulate human IgE synthesis.

A new pair of surface molecules involved in human IgE regulation

The molecules controlling IgE production are the subject of intense study in the effort to find new ways to treat allergic diseases. One candidate, the CD23 molecule, a low affinity receptor for IgE, was recently identified to interact with another molecule, named CD21, in the regulation of IgE production.

Critical role of CD23 in allergen-induced bronchoconstriction in a murine model of allergic asthma

CD23‐deficient and anti‐CD23 monoclonal antibody‐treated mice were used to investigate the role of the low‐affinity receptor for IgE (CD23) in allergic airway inflammation and airway hyperresponsiveness (AHR). While there were no significant differences in ovalbumin (OVA)‐specific IgE titers and tissue eosinophilia, evaluation of lung function demonstrated that CD23− / − mice showed an increased AHR to methacholine (MCh) when compared to wild‐type mice but were completely resistant to the OVA challenge. Anti‐CD23 Fab fragment treatment of wild‐type mice did not affect the MCh‐induced AHR but significantly reduced the OVA‐induced airway constriction. These results imply a novel role for CD23 in lung inflammation and suggest that anti‐CD23 Fab fragment treatment may be of therapeutic use in allergic asthma.

Receptors for IgE.

Following advances during the past 5 years in our understanding of the molecular structure of receptors for IgE, progress has been made in elucidating the structure and function of IgE receptors and the signalling events through these receptors. IgE is not the only ligand for some of these receptors, leading to their having unexpected and interesting biological activities.