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

Abstract

During viremia, the HIV-specific memory response in lymph nodes is mediated by T-bethi B cells that inefficiently participate in affinity selection. Abrogated antibody responses in chronic infection Despite the presence of abundant and persistent antigen, chronic infections such as HIV often do not induce protective antibody responses. Memory B cells from people chronically infected with HIV have previously been reported to express the transcription factor T-bet. Austin et al. observed that T-bethi memory B cells were in the lymph nodes but not localized to germinal centers, where high-affinity antibody responses develop. Although clonally related to germinal center B cells, these T-bethi memory B cells had a lower frequency of somatic hypermutation and reduced capacity to neutralize HIV in vitro. Exclusion of T-bethi memory cells from germinal centers may be one mechanism contributing to the lack of a protective antibody response in most HIV infections. 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.