gp39-CD40 interactions are essential for germinal center formation and the development of B cell memory.

Abstract

Summarygp39, the ligand for CD40 expressed on activated CD4 + T helper cells, is required for the generation of antibody responses to T-dependent (TD) antigens. Treatment of mice with antigp39 in vivo inhibits both primary and secondary antibody formation to TD, but not T-independent antigens. However, the role of this receptor-ligand pair in the development of germinal centers and the generation of B cell memory is as yet undefined. Using an antibody to gp39, this study examines the in vivo requirement for gp39-CD40 interactions in the induction of germinal center formation, as well as in the generation of B cell memory. Animals were immunized, treated in vivo with anti-gp39, and evaluated using immunohistochemical staining for the presence of splenic germinal centers 9-11 d after immunization. The results demonstrate that the formation of germinal centers was completely inhibited as a result of treatment with anti-gp39. Moreover, adoptive transfer experiments demonstrate that the generation of antigen-specific memory B cells is also inhibited as a consequence of blocking gp39-CD40 interactions. Taken together, the data demonstrate that gp39-CD40 interactions are critical not only for the generation of antibody responses, but also in the development of B cell memory.

T follicular helper expansion and humoral-mediated rejection are independent of the HVEM/BTLA pathway

“…Antibodies for in vivo use and flow cytometry Hybridoma cell lines that secreted an anti-HVEM monoclonal antibody (mAb) (clone 6C9, blocking antibody of the HVEM/ BTLA interaction), 20 anti-BTLA mAb (clone 4G12b, downmodulates BTLA receptor expression), 21,27 anti-CD40L mAb (clone MR1, blocking/depleting antibody) [28][29][30] or an isotype-matched control rat IgG 2a (antiplant cytokinin, clone AFRC-MAC-157) antibody were grown in Serum free medium (SFM) medium Gibco (Grand Island, NY 14072, USA) supplemented with IgG-depleted foetal calf serum (less than 1%) in spinner flasks. Cell culture supernatants were pre-filtered and then loaded onto a protein G-Sepharose column, and affinity chromatography was performed for the purification of the immunoglobulins.…”

Early reduction of the over-expression of CD40L, OX40 and Fas on T cells in HIV-1 infection during triple anti-retroviral therapy: possible implications for lymphocyte traffic and functional recovery

“…CD40L was initially described as a molecule critical for B cell activation and immunoglobulin isotype switching [20], but it is now recognized that its function extends much beyond, with effects on T cells [22], dendritic cells and macrophages [23] as well as on endothelial cells [26]. Thus, the CD40L/CD40 pathway became a major target for possible immunological therapy in allograft transplantation, GVHD, and in several autoimmune diseases [30,31], particularly in SLE, where the high levels of circulating CD4 T cells expressing CD40L have been correlated with disease activity [28].…”

“…Fas (CD95, APO-1)/Fas ligand is a key cellular apoptotic pathway involved in the physiologic regulation of immune responses [18], which has Clin Exp Immunol 1999; 116:307-315 been proposed to play a role in HIV-associated lymphocyte anergy and programmed cell death [19]. On the other hand, CD40L (CD154 or gp39) and OX40 (CD134) are molecules transiently expressed on the surface of T cells upon activation with fundamental roles on T-B cell interactions [20,21], as well as important effects on T cell differentiation [22] and on dendritic cell maturation [23,24]. Furthermore, they promote endothelial cell activation and expression of adhesion molecules that contribute to regulate leucocyte traffic and inflammatory responses [25,26].…”

The Pleckstrin Homology Domain Adaptor Protein Bam32/DAPP1 Is Required for Germinal Center Progression

“…GC B cells are highly prone to apoptosis, but can be rescued from apoptosis in culture by stimulation through either CD40 or the BCR (6). Maintenance of GC responses, as well as generation of memory B cells, depends on signaling via CD40L and other T cellderived signals (7)(8)(9)(10)(11). Under some unusual circumstances, GC responses can be initiated in the absence of T cell help; however, these GCs are short-lived and abort prematurely without giving rise to affinity maturation (12,13), underlining the critical importance of T cell-derived signals in sustaining the GC response through the critical selection period.…”