CD40 Signaling Drives B Lymphocytes Into an Intermediate Memory‐Like State, Poised Between Naïve and Plasma Cells

Abstract

Immunological memory comprising of antigen-specific B and T cells contributes to the acquisition of long-term resistance to pathogens. Interactions between CD40 on B cells and CD40L on T cells are responsible for several aspects of acquired immune responses including generation of memory B cells. In order to gain insights into events leading to memory B cell formation, we analyzed the genome-wide expression profile of murine naive B cells stimulated in the presence of anti-CD40. We have identified over 8,000 genes whose expression is altered minimally 1.5-fold at least at one time point over a 3-day time course. The array analysis indicates that changes in expression level of maximum number of these genes occur within 24 h of anti-CD40 treatment. In parallel, we have studied the events following CD40 ligation by examining the expression of known regulators of naive B cell to plasma cell transition, including Pax5 and BLIMP1. The expression profile of these regulatory genes indicates firstly, that CD40 signaling activates naïve B cells to a phenotype that is intermediate between the naive and plasma cell stages of the B cell differentiation. Secondly, the major known regulator of plasma cell differentiation, BLIMP1, gets irreversibly downregulated upon anti-CD40 treatment. Additionally, our data reveal that CD40 signaling mediated BLIMP1 downregulation occurs by non-Pax5/non-Bcl6 dependent mechanisms, indicating novel mechanisms at work that add to the complexity of understanding of B cell master regulatory molecules like BLIMP1 and Pax5.

CTCF orchestrates the germinal centre transcriptional program and prevents premature plasma cell differentiation

“…6a), since signalling through the CD40 receptor has been shown to downregulate Blimp-1 levels in B cells353637. qRT-PCR analysis confirmed once again that CTCF-deficient B cells have higher Blimp-1 expression levels than their littermate controls (Fig.…”

Dual targeting: Combining costimulation blockade and bortezomib to permit kidney transplantation in sensitized recipients

“…22 In addition, treatment with bortezomib alone resulted in rebound GC response including increased class-switched B cell proliferation and Tfh cells. 22 Belatacept and anti-CD40mAb have been shown to prevent antigen-specific antibody formation in small animals 29,30 and in nonsensitized transplant recipients. 31 We have seen similar effects from belatacept/2C10.R4 on de novo DSA production and GC responses in a NHP model of de novo AMR.…”

“…28 Nevertheless, the DSA reduction contrasted with data using bortezomib monotherapy (Table S1), which showed profound BM PC reduction but no DSA decrease. 30 However, CoB without bortezomib did not reduce BM PCs in sensitized animals. 22 Belatacept and anti-CD40mAb have been shown to prevent antigen-specific antibody formation in small animals 29,30 and in nonsensitized transplant recipients.…”

“…As shown in Figure 4E, GC staining appeared earlier in control animals compared to desensitized recipients. 22 Belatacept and anti-CD40mAb have been shown to prevent antigen-specific antibody formation in small animals 29,30 and in nonsensitized transplant recipients. This suggests the desensitization strategy suppressed GC reconstitution after T cell depletion, but allowed GC responses later with a lack of antidonor antibody response.…”

B Cell-Based Cancer Immunotherapy

“…When PBMCs are used as the starting material, typically B-cell purities of more than 95% can be achieved. Throughout the culture period, B cells acquire a memory-like state that represents an intermediary stage between naïve B cells and plasma cells [39]. B cells that are stimulated for at least 3 days by the CD40L show a high expression of MHC class I and MHC class II molecules, the costimulatory markers CD80, CD83, and CD86, and the adhesion molecules CD54 and CD58, which remains stable throughout the subsequent culture period [15, 18, 35, 37, 38].…”