Viral subversion of B cell responses within secondary lymphoid organs

Abstract

Antibodies play a crucial role in virus control. The production of antibodies requires virus-specific B cells to encounter viral antigens in lymph nodes, become activated, interact with different immune cells, proliferate and enter specific differentiation programmes. Each step occurs in distinct lymph node niches, requiring a coordinated migration of B cells between different subcompartments. The development of multiphoton intravital microscopy has enabled researchers to begin to elucidate the precise cellular and molecular events by which lymph nodes coordinate humoral responses. This Review discusses recent studies that clarify how viruses interfere with antibody responses, highlighting how these mechanisms relate to our topological and temporal understanding of B cell activation within secondary lymphoid organs.

Figure 1. Spatiotemporal dynamics of B cell activation.

The structure of a lymph node, showing the subcapsular sinus (SCS), T cell area and B cell follicle (left-hand side). Viruses drained by afferent lymph (right-hand side) are captured and retained by SCS macrophages (SSMs), which shuttle the virus across their surface towards naive B cells in the underlying follicle (step 1). Upon encounter with the antigen, naive B cells undergo early activation and proliferation and relocalize to the B cell–T cell boundary to search for T cell help (step 2). Interaction with cognate CD4⁺ T cells leads antigen-specific B cells either to differentiate into short-lived plasma cells secreting low-affinity antibodies (step 3) or to localize back to the follicle and enter a germinal centre reaction (step 4). During germinal centre reactions, antigen-specific B cells engage in interactions with T follicular helper cells and antigens (retained by follicular dendritic cells) and undergo an affinity maturation process, which ultimately results in the production of high-affinity neutralizing antibodies. HEV, high endothelial venule.

Figure 2. Viral interference with early B cell activation.

The encounter of B cells with viruses can lead to B cell death or functional inhibition. a | Influenza virus can infect antigen-specific B cells via a haemagglutinin (HA)-specific B cell receptor (BCR) and induce their apoptosis. b | HIV binding to B cells (left) via viral envelope glycoprotein gp120–cellular α4β7 integrin interaction leads to overexpression of transforming growth factor-β1 (TGFβ1) and the inhibitory receptor Fc receptor-like protein 4 (FcRL4) that hinder B cell proliferation. Epstein–Barr virus (EBV)-derived latent membrane protein 2A (LMP2A) sequesters the tyrosine-protein kinases LYN and SYK (middle), thereby inhibiting BCR signalling. The interaction of hepatitis C virus (HCV)-derived E2 glycoprotein with CD81 on B cells (right) leads to polyclonal expansion of B cells and inhibition of antigen-specific BCR signalling. CR2, complement receptor type 2.

Figure 3. Inflammatory monocytes hinder antiviral B cell responses.

Upon lymphocytic choriomeningitis virus (LCMV) infection (left), antigen-specific B cells encounter the virus, upregulate early activation markers and relocalize from the centre of the follicle to the interfollicular area (IFA) and T cell area of the lymph node. Viral replication induces a type-I-interferon-dependent CC-chemokine ligand 2 (CCL2) gradient (middle), which attracts CC-chemokine receptor 2 (CCR2)-positive inflammatory monocytes to the virus-draining lymph node. Inflammatory monocytes localize to the IFAs, where they interact with LCMV-specific activated B cells. Following this interaction (right), LCMV-specific B cell responses are inhibited owing to apoptosis induced in B cells through a nitric oxide (NO)-dependent mechanism. SSM, subscapular sinus macrophage.

Figure 4. Viral subversion of B cell responses in germinal centres.

Some viruses can affect the process of immunoglobulin class switching and somatic hypermutation in the dark zone. For example, the hepatitis C virus (HCV) protein E2 can interact with CD81 on B cells to induce polyclonal nonspecific hypermutation, thus reducing the affinity of HCV-specific antibodies. Similarly, HIV glycoprotein gp120 can bind to mannose C-type lectin receptor (MR) and induces the B cell expression of activation-induced cytidine deaminase (AID), leading to polyclonal hypermutation. In addition, HIV-derived negative factor protein Nef can penetrate B cells and suppress immunoglobulin class switching via induction of IκBα (NF-κB inhibitor-α) and suppressors of cytokine signalling (SOCS) proteins, which block CD40 signalling. Viruses can also interfere with B cell activation in the light zone. For example, bluetongue virus (BTV) can infect and kill follicular dendritic cells (FDCs), thereby causing germinal centre (GC) disruption. CD40L, CD40 ligand.

Figure 5. Type I interferon-mediated suppression of antibody responses.

Sustained type I interferon and subsequent CC-chemokine ligand 2 (CCL2) production leads to the recruitment of inflammatory monocytes to the virus-draining lymph node; inflammatory monocytes interact with and inhibit lymphocytic choriomeningitis virus (LCMV)-specific B cell responses by inducing apoptosis in a nitric oxide (NO)-dependent fashion. Type I interferon sustains expansion and differentiation of CD8⁺ T lymphocytes, which interact with LCMV-specific B cells and directly kill them upon secretion of cytolytic granules. Finally, type I interferon induces an inflammatory milieu (including tumour necrosis factor (TNF) and IL-10 secretion by different cell types) that triggers differentiation of activated LCMV-specific B cells into short-lived plasma cells, eventually resulting in B cell apoptosis. CTL, cytotoxic T lymphocyte; DC, dendritic cell.