Short-circuiting long-lived humoral immunity by the heightened engagement of CD40 - PubMed (original) (raw)

Short-circuiting long-lived humoral immunity by the heightened engagement of CD40

Loren D Erickson et al. J Clin Invest. 2002 Mar.

Abstract

Agonistic alpha CD40 Ab's have been shown to be potent immune adjuvants for both cell- and humoral-mediated immunity. While enhancing short-lived humoral immunity, the administration of a CD40 agonist during thymus-dependent immune responses ablates germinal center formation, prematurely terminates the humoral immune response, blocks the generation of B cell memory, and prevents the generation of long-lived bone marrow plasma cells. Interestingly, some of these effects of heightened CD40 engagement could be mimicked by enhancing the magnitude of antigen-specific T cell help. Taken together, these studies demonstrate that as the magnitude of CD40 signaling intensifies, the fate of antigen-reactive B cells can be dramatically altered. These are the first studies to describe the multifaceted function of CD40 in determining the fate of antigen-reactive B cells and provide novel insights into how CD40 agonists can short-circuit humoral immunity.

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Figures

Figure 1

Figure 1

αCD40 treatment aborts a GC phenotype and promotes extrafollicular localization of Tg B cells. (a) Total numbers of splenic Tg B cells (anti-NP idiotype+, B220+) were measured on day 7 after immunization. (b) Spleen or LN cells from naive (black line), immune/RIgG (red line), and immune/αCD40 (blue line) were stained with GC markers. Histograms shown represent the relative intensity of the indicated marker on Tg B cells (B220+ Id+). (c) Spleen cells from naive and immune IghCD40 transgenic mice treated with rat IgG or agonistic αhCD40 mAb were stained with GC markers. The percentage of total PNA+ GL7+ GC B cells are indicated in each panel. (d) Frozen sections from intact spleens were costained with B220 (green), CD4, and CD8 (red), and anti–NP idiotype (Id) 17.2.25 (blue) Ab’s, and analyzed by confocal microscopy. Objective: ×20; zoom 1.5. Data are representative of three independent experiments.

Figure 2

Figure 2

Administration of αCD40 reduces the duration of humoral immune responses. Serum αNP IgG1a levels were measured by ELISA on days indicated after immunization. Values are a composite of three mice per group. Data are representative of three experiments.

Figure 3

Figure 3

αCD40 administration prevents the generation of bone marrow ASCs. Cells from spleen and bone marrow were isolated from the indicated recipients on day 7 (a) and day 21 (b) after immunization and assayed for total NP-specific IgG1a or high-affinity NP-specific IgG1a (c) by ELISPOT using normalized numbers of Tg B cells. Results shown are representative of three independent experiments.

Figure 4

Figure 4

Administration of αCD40 upregulates Blimp-1 gene expression in Tg B cells. PCR amplification of the indicated transcript was performed using normalized amounts of cDNA isolated from purified splenic Tg B cells of recipients challenged with NP-Ficoll (TI immune), NP-KLH (TD immune), or NP-KLH and treated with αCD40 (TD immune + αCD40). Data are representative of three mice per group from two independent experiments.

Figure 5

Figure 5

Carrier-primed T cells prevent the acquisition of a GC phenotype in the spleen but not in the LN and differentially control the generation of long-lived Tg ASCs. (a) Total numbers of LN and splenic Tg B cells were quantified 5 days after challenge. (b) Tg cells from naive (shaded area) and immune (open area) recipients were stained for the expression of the indicated GC marker. Histograms shown represent the relative intensity on gated Tg cells isolated from LN and spleen. Data are representative of six experiments. (c) Frozen sections from intact spleen and LN were costained with B220 (green), CD4 and CD8 (red), and anti–NP Id 17.2.25 (blue) Ab’s, followed by confocal image analysis. Objective: ×20; zoom: 1.75. (d) Equivalent numbers of naive and immune Tg B cells isolated from spleen and LN of carrier-primed recipients were transferred into secondary recipients that received neither priming nor antigen. Total numbers of bone marrow NP-specific IgG1a ASCs were quantified by ELISPOT analysis 7 days after transfer. Data shown are representative of three independent experiments.

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