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Overexpression of T-bet in HIV infection is associated with accumulation of B cells outside germinal centers and poor affinity maturation.
- Source :
-
Science translational medicine [Sci Transl Med] 2019 Nov 27; Vol. 11 (520). - Publication Year :
- 2019
-
Abstract
- Nearly all chronic human infections are associated with alterations in the memory B cell (MBC) compartment, including a large expansion of CD19 <superscript>hi</superscript> T-bet <superscript>hi</superscript> 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 <superscript>hi</superscript> 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 <superscript>hi</superscript> B cells of HIV-infected individuals were almost exclusively found among CD19 <superscript>hi</superscript> MBC and expressed reduced GC-homing receptors. Furthermore, HIV-specific B cells of infected individuals were enriched among LN CD19 <superscript>hi</superscript> T-bet <superscript>hi</superscript> MBC and displayed a distinct transcriptome, with features similar to CD19 <superscript>hi</superscript> T-bet <superscript>hi</superscript> MBC in blood and LN GC B cells (GCBC). LN CD19 <superscript>hi</superscript> T-bet <superscript>hi</superscript> 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.<br /> (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Subjects :
- Adult
Antibodies, Neutralizing immunology
Antigens, CD19 metabolism
Cytokines metabolism
Female
HIV Infections genetics
Humans
Immunologic Memory
Lymph Nodes pathology
Male
Middle Aged
Mutation Rate
Phenotype
Receptors, Antigen, B-Cell metabolism
T-Lymphocytes, Helper-Inducer immunology
Transcriptome genetics
Young Adult
Antibody Affinity immunology
B-Lymphocytes immunology
Germinal Center immunology
HIV Infections immunology
T-Box Domain Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1946-6242
- Volume :
- 11
- Issue :
- 520
- Database :
- MEDLINE
- Journal :
- Science translational medicine
- Publication Type :
- Academic Journal
- Accession number :
- 31776286
- Full Text :
- https://doi.org/10.1126/scitranslmed.aax0904