LIGHT costimulates CD40 triggering and induces immunoglobulin secretion; a novel key partner in T cell‐dependent B cell terminal differentiation

Abstract

The T cell-dependent differentiation and function of B lymphocytes are tightly regulated by TNF ligands (L) and receptors interactions, such as CD40/CD40L, CD27/CD70 and CD134/ CD314L. The LIGHT/HVEM system [homologous to lymphotoxin, inducible expression, competing for GpD of herpes virus, that binds to the herpes virus entry mediator (HVEM), and is expressed on activated T lymphocytes) focused our attention since HVEM has a large distribution that, in addition to T cells, DC or NK, includes tumor and normal B lymphocytes. HVEM was expressed on memory and naive B cells from peripheral blood or tonsils, but not on germinal center (GC) B cells. Costimulation by CD40L+LIGHT induced LIGHT expression at the B lymphocyte surface by a transcriptional mechanism since we detected de novo expression of LIGHT-specific mRNA. LIGHTexpression was further enhanced by triggering of surface IgM, a stimulus that mimics a normal step of B cell physiology, i.e. specific antigen encounter. Stimulation by LIGHT increased the B cell proliferation induced by CD40L, and induced IgG and IgM (but not IgA) secretion. We conclude that LIGHT costimulation, that mimics the B cell encounter with activated LIGHT-expressing T lymphocytes, enhances both B cell proliferation and Ig production, and thus has a central importance for humoral immunity development.

A role for HVEM, but not lymphotoxin‐β receptor, in LIGHT‐induced tumor cell death and chemokine production

“…As previously reported, CD40L did not induce B-CLL cell death (22.672%). Finally, we also tested CD40L/LIGHT costimulation because we had previously shown that these two molecules act in cooperation for B-lymphocyte proliferation [17]. Here, CD40L/LIGHT costimulation gave a similar effect to LIGHT alone; thus neither does CD40L appear to cooperate with LIGHT to induce cell death nor hinders it.…”

“…[23]. In this study we investigated the effects of LIGHT in hematopoietic malignancies and we chose to focus on B-CLL, given the strong expression of HVEM in these cells and our previous results on the importance of LIGHT in the physiology of B lymphocytes [17]. Thus, to explore the impact of LIGHT in this lymphoid malignancy, we stimulated B-CLL cells with an anti-HVEM mAb and performed a QRT-PCR global analysis of the expression of a large panel of genes.…”

“…Given the strong expression of HVEM in chronic lymphocytic leukemia (CLL) cells and our previous experience on the effects of LIGHT in both normal [17] and mantle-cell lymphoma [29] B lymphocytes, we focused our attention on the analysis of the effect of LIGHT stimulation on B-CLL cells. Here, we studied the effect of LIGHT and HVEM first on the transcriptional regulation of a number of genes coding for chemokines, chemokine receptors, cytokines, and molecules involved in adhesion, migration, or apoptosis.…”

“…Blockade of endogenous LIGHT efficiently prevents the development of T-cell-mediated graft-versushost disease [10][11][12]13]. Moreover, LIGHT and CD40L act synergistically to induce dendritic cell maturation, LIGHT protein induction at the surface of B lymphocytes, and B-cell proliferation [14][15][16][17]. In contrast, biological consequences of LIGHT/LTbR signaling include apoptosis of adenocarcinoma when combined with IFN-g [18,19], but also organization and maintenance of lymphoid structures [20,21], partly because of its ability to induce the expression of various chemokines and adhesion molecules [22].…”

Regulation of cell fate by lymphotoxin (LT) receptor signalling: Functional differences and similarities of the LT system to other TNF superfamily (TNFSF) members

“…Two studies in vitro showed that LIGHT induces T cell proliferation, IFN-γ secretion and NF-B activation (101,102). LIGHT also cooperates with CD40 ligand (CD154) contributing to DC maturation (103)(104)(105). LIGHT induces the …”