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

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TitleOverexpression of T-bet in HIV infection is associated with accumulation of B cells outside germinal centers and poor affinity maturation.
Publication TypeJournal Article
Year of Publication2019
AuthorsAustin, JW, Buckner, CM, Kardava, L, Wang, W, Zhang, X, Melson, VA, Swanson, RG, Martins, AJ, Zhou, JQ, Hoehn, KB, J Fisk, N, Dimopoulos, Y, Chassiakos, A, O'Dell, S, Smelkinson, MG, Seamon, CA, Kwan, RW, Sneller, MC, Pittaluga, S, Doria-Rose, NA, McDermott, A, Li, Y, Chun, T-W, Kleinstein, SH, Tsang, JS, Petrovas, C, Moir, S
JournalSci Transl Med
Volume11
Issue520
Date Published2019 Nov 27
ISSN1946-6242
Abstract

Nearly all chronic human infections are associated with alterations in the memory B cell (MBC) compartment, including a large expansion of CD19T-bet 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-bet 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-bet B cells of HIV-infected individuals were almost exclusively found among CD19 MBC and expressed reduced GC-homing receptors. Furthermore, HIV-specific B cells of infected individuals were enriched among LN CD19T-bet MBC and displayed a distinct transcriptome, with features similar to CD19T-bet MBC in blood and LN GC B cells (GCBC). LN CD19T-bet 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.

DOI10.1126/scitranslmed.aax0904
Alternate JournalSci Transl Med
PubMed ID31776286