Impact of BAFF Blockade on Inflammation, Germinal Center Reaction and Effector B-Cells During Acute SIV Infection.

Gwenoline Borhis,Roger Le Grand,Nathalie Bosquet,Maria Trovato,Hany M Ibrahim,Yolande Richard,Stephane Isnard

doi:10.3389/fimmu.2020.00252

Abstract

Memory B-cell dysfunctions and inefficient antibody response suggest germinal center (GC) impairments during HIV/SIV infection with possible contribution of overproduced B-cell activating factor (BAFF). To address this question, we compared proportions and functions of various B-cell subsets and follicular helper T-cells (TFH) in untreated (Placebo) and BR3-Fc treated (Treated) SIV-infected macaques. From day 2 post-infection (dpi), Treated macaques received one weekly injection of BR3-Fc molecule, a soluble BAFF antagonist, for 4 weeks. Whereas, the kinetics of CD4+ T-cell loss and plasma viral loads were comparable in both groups, BAFF blockade delayed the peak of inflammatory cytokines (CXCL10, IFNα), impaired the renewal of plasmacytoid dendritic cells and fostered the decline of plasma CXCL13 titers after 14 dpi. In Treated macaques, proportions of total and naïve B-cells were reduced in blood and spleen whereas SIV-induced loss of marginal zone (MZ) B-cells was only accentuated in blood and terminal ileum. Proportions of spleen GC B-cells and TFH were similar in both groups, with CD8+ T-cells and rare Foxp3+ being present in spleen GC. Regardless of treatment, sorted TFH produced similar levels of IL21, CXCL13, and IFNγ but no IL2, IL4, or BAFF and exhibited similar capacities to support IgG production by autologous or heterologous B-cells. Consistently, most TFH were negative for BAFF-R and TACI. Higher proportions of resting and atypical (CD21lo) memory B-cells were present in Treated macaques compared to Placebo. In both groups, we found higher levels of BAFF-R expression on MZ and resting memory B-cells but low levels on atypical memory B-cells. TACI was present on 20-30% of MZ, resting and atypical memory B-cells in Placebo macaques. BAFF blockade decreased TACI expression on these B-cell subsets as well as titers of SIV-specific and vaccine-specific antibodies arguing for BAFF being mandatory for plasma cell survival. Irrespective of treatment, GC B-cells expressed BAFF-R at low level and were negative for TACI. In addition to key information on spleen BAFF-R and TACI expression, our data argue for BAFF contributing to the GC reaction in terminal ileum but being dispensable for the generation of atypical memory B-cells and GC reaction in spleen during T-dependent response against SIV.

Highlights

Optimal protection against numerous pathogens requires humoral memory response with the rapid development of neutralizing antibodies (Abs) and the generation of pathogenspecific effector B cells in germinal centers (GC)
BAFF blockade did not change the kinetics of plasma viral load (Figure 1C), which peaked at 10 dpi in both groups (7.46 ± 1.93 × 106 and 9.71 ± 1.67 × 106 RNA copies/ml in Placebo and Treated macaques, respectively)
Given that BAFF is a key cytokine for GC maintenance in mice [31, 32] but its excess favors autoimmunity [46, 47], we hypothesized that blockade of the BAFF excess reported during the acute phase of Simian Immunodeficiency virus (SIV) infection [40] might “reset” the GC reaction and initiate a more effective virus-specific response

Summary

Introduction

Optimal protection against numerous pathogens requires humoral memory response with the rapid development of neutralizing antibodies (Abs) and the generation of pathogenspecific effector B cells (long-lived plasma blasts and memory B-cells) in germinal centers (GC). Cross-neutralizing Abs with narrow breadth are present during the 1st year of infection in high numbers of HIV-infected individuals [4], but only a minority of individuals develops potent broadly neutralizing Abs after years of infection These Abs generally harbor features of self/poly-reactivity and high levels of somatic hyper-mutations in immunoglobulin (Ig) genes, arguing for their T-dependent (TD) affinity maturation and selection in GC [5,6,7]. First considered as exhausted B-cells due to the expression of FcRL5/4 and PD1 [12], TLM B-cells are thought to be short-lived, early plasma blasts or recent GC emigrants that are maintained by repetitive antigen exposure during chronic infection and physiologically during vaccination [13]. Functional HIV-specific memory Bcells are associated with efficient viral neutralization in Elite controllers [10, 15], and significant recovery of HIV-specific RM B-cells requires initiation of anti-retroviral therapy as soon as the acute phase of infection [16]

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Results

Conclusion