Regulation of Subunit-Specific Germinal Center B Cell Responses to the HIV-1 Envelope Glycoproteins by Antibody-Mediated Feedback.

Mattias N E Forsell,John Andersson,Linda Kvastad,Mikael C I Karlsson,Saikiran K Sedimbi

doi:10.3389/fimmu.2017.00738

Mattias N E Forsell, John Andersson + Show 3 more

Open Access

https://doi.org/10.3389/fimmu.2017.00738

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Abstract

The regulation of germinal center (GC) B cell responses to single epitopes is well investigated. How monoclonal B cells are regulated within the polyclonal B cell response to protein antigens is less so. Here, we investigate the primary GC B cell response after injection of mice with HIV-1 envelope glycoproteins. We demonstrate that single GCs are seeded by a diverse number of B cell clones shortly after a single immunization and that the presence of Env-specific antibodies can inhibit the development of early GC B cells. Importantly, the suppression was dependent on the GC B cells and the infused antibodies to target the same subunit of the injected HIV-1 envelope glycoproteins. An affinity-dependent antibody feedback has previously been shown to regulate GC B cell development. Here, we propose that this antibody-based feedback acts on GC B cells only if they target the same or overlapping epitopes. This study provides important basic information of GC B cell regulation, and for future vaccine designs with aim to elicit neutralizing antibodies against HIV-1.

Highlights

There is abundant evidence that some HIV-1-infected patients develop broadly neutralizing antibodies at the chronic stage of the infection [1, 2]
To determine if potent germinal center (GC) B cell responses occur after a single injection with envelope glycoproteins (Env), we devised an injection regimen to characterize the development of GC B cells after immunization with Env in Imject AlumTM adjuvant
We could quantify the overall reduction of GC B cells between days 11 and 21 after immunization Collectively, these data verify that GC B cell responses develop after a single injection of mice with Env in adjuvant

Summary

Introduction

There is abundant evidence that some HIV-1-infected patients develop broadly neutralizing antibodies (bNabs) at the chronic stage of the infection [1, 2]. This demonstrates that the human immune system is, under certain circumstances, capable to produce antibodies that may be useful if they could be re-elicited by vaccination. It has been postulated that humoral immune responses to immunodominant regions of Env may suppress responses to less immunogenic regions, and that this could explain why bNabs are infrequently elicited during infection and has, to date, not been elicited by vaccination. In GCs, antigen-specific B cells undergo affinity maturation and differentiation into memory B cells and Subunit-Specific GC B Cell Responses

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