Overexpression of T-bet in HIV infection is associated with accumulation of B cells outside germinal centers and poor affinity maturation

JW Austin, CM Buckner, L Kardava, W Wang… - Science translational …, 2019 - science.org
JW Austin, CM Buckner, L Kardava, W Wang, X Zhang, VA Melson, RG Swanson, AJ Martins
Science translational medicine, 2019science.org
Nearly all chronic human infections are associated with alterations in the memory B cell
(MBC) compartment, including a large expansion of CD19hiT-bethi MBC in the peripheral
blood of HIV-infected individuals with chronic viremia. Despite their prevalence, it is unclear
how these B cells arise and whether they contribute to the inefficiency of antibody-mediated
immunity in chronic infectious diseases. We addressed these questions by characterizing T-
bet–expressing B cells in lymph nodes (LN) and identifying a strong T-bet signature among …
Nearly all chronic human infections are associated with alterations in the memory B cell (MBC) compartment, including a large expansion of CD19hiT-bethi MBC in the peripheral blood of HIV-infected individuals with chronic viremia. Despite their prevalence, it is unclear how these B cells arise and whether they contribute to the inefficiency of antibody-mediated immunity in chronic infectious diseases. We addressed these questions by characterizing T-bet–expressing B cells in lymph nodes (LN) and identifying a strong T-bet signature among HIV-specific MBC associated with poor immunologic outcome. Confocal microscopy and quantitative imaging revealed that T-bethi B cells in LN of HIV-infected chronically viremic individuals distinctly accumulated outside germinal centers (GC), which are critical for optimal antibody responses. In single-cell analyses, LN T-bethi B cells of HIV-infected individuals were almost exclusively found among CD19hi MBC and expressed reduced GC-homing receptors. Furthermore, HIV-specific B cells of infected individuals were enriched among LN CD19hiT-bethi MBC and displayed a distinct transcriptome, with features similar to CD19hiT-bethi MBC in blood and LN GC B cells (GCBC). LN CD19hiT-bethi MBC were also related to GCBC by B cell receptor (BCR)–based phylogenetic linkage but had lower BCR mutation frequencies and reduced HIV-neutralizing capacity, consistent with diminished participation in GC-mediated affinity selection. Thus, in the setting of chronic immune activation associated with HIV viremia, failure of HIV-specific B cells to enter or remain in GC may help explain the rarity of high-affinity protective antibodies.
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