T-bet+ B cells are induced by human viral infections and dominate the HIV gp140 response

Knox, James J.; Buggert, Marcus; Kardava, Lela; Seaton, Kelly E.; Eller, Michael A.; Canaday, David H.; Robb, Merlin L.; Ostrowski, Mario; Deeks, Steven G.; Slifka, Mark K.; Tomaras, Georgia D.; Moir, Susan; Moody, M. Anthony; Betts, Michael R.

doi:10.1172/jci.insight.92943

Cited by 151 publications

(257 citation statements)

References 78 publications

(97 reference statements)

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Section: T-bet+ B Cells As An Antiviral Populationmentioning

confidence: 99%

“…1 and [13]). This latter population was characterized as a transcriptionally distinct memory B cell subset with an activated phenotype and a specific homing receptor profile (CD11c + CXCR3 + ; [13]). Further, we observed enrichment of IgG1 and IgG3 isotypes (human homologues of mouse IgG2a/c) in total T-bet + B cells, suggesting a similar regulation of antiviral isotype switching in human B cells by T-bet and parallel roles for T-bet + B cells in humans and mice [13].…”

Section: T-bet+ B Cells As An Antiviral Populationmentioning

confidence: 99%

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T-bet-expressing B cells during HIV and HCV infections

Knox

Kaplan

Betts

2017

Cellular Immunology

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T-bet-expressing B cells, first identified as perpetuators of autoimmunity, were recently shown to be critical for murine antiviral responses. While their role in human viral infections remains unclear, B cells expressing T-bet or demonstrating a related phenotype have been described in individuals chronically infected with HIV or HCV, suggesting these cells represent a component of human antiviral responses. In this review, we discuss the induction of T-bet in B cells following both HIV and HCV infections, the factors driving T-bet+ B cell expansions, T-bet’s relationship to atypical memory B cells, and the consequences of T-bet induction. We propose potential antiviral roles for T-bet+ B cells and discuss whether this population poses any utility to the HIV and HCV immune responses.

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Section: T-bet+ B Cells As An Antiviral Populationmentioning

confidence: 99%

Section: T-bet+ B Cells As An Antiviral Populationmentioning

confidence: 99%

T-bet-expressing B cells during HIV and HCV infections

Knox

Kaplan

Betts

2017

Cellular Immunology

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“…Similarly, viral infections, or nucleic acid-based antigens would elicit a Th1 response, where IFNγ and IL-21 together would promote increased T-bet expression in a TLR-dependent manner, enabling class switching to IgG 2a/c and other T-bet-associated characteristics. Indeed, an increasing body of literature implicates T-bet expressing B cells in a variety of infections, including influenza [30], LCMV [33], HCV [34], and HIV [35][36]. …”

Section: Signals Driving T-bet In B Cellsmentioning

confidence: 99%

Signals that drive T-bet expression in B cells

Myles

Gearhart

Cancro

2017

Cellular Immunology

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Transcription factors regulate various developmental and functional aspects of B cells. T-bet is a recently appreciated transcription factor associated with “Age-associated B cells” or ABCs, the development of autoimmunity, and viral infections. T-bet expression is favored by nucleic acid-containing antigens and immune complexes and is regulated by interplay between various cytokines, notably, the TFH cytokines IL-21, IL-4 and IFNγ. Adaptive signals by themselves cannot upregulate T-bet; however, they have a synergistic effect on induction of T-bet by innate receptors. The functional role of T-bet + B cells is unclear, although it is known that T-bet promotes class switching to IgG2a/c. It is likely T-bet serves dichotomous roles in B cells, promoting pathogenic autoreactive antibodies on one hand but mediating microbial immunity on the other, making it a target of interest in both therapeutic and prophylactic settings.

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“…ixed cryoglobulinemia is one of several B-cell proliferative disorders that may result from chronic hepatitis C infection, and it is thought to be driven by expansion of HCV envelope-specific B cells that preferentially use immunoglobulin gene segments V H 1-69 and V k [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]3 and to evolve rheumatoid factor activity through somatic hypermutation.…”

mentioning

confidence: 99%

“…Recent data suggest that the T-box expressed in T cells (T-bet) transcription factor, critical for inducing sterilizing humoral immunity in acute infections, 6 may also regulate the exhausted state in both autoreactive 7 and antigeninduced anergic B cells. 8,9 No data to date specifically link the anergy properties observed in cryoglobulin-producing B cells and T-bet, but there are phenotypic similarities (CD11c 1 /CD21 low ) that suggest a possible relationship that should be explored; rapid upregulation of T-bet in convalescent CD21 low B cells upon reexposure to autologous HCV strains ex vivo has been observed, 8 suggesting a link between B-cell receptor ligation, T-bet, and the CD21 low exhaustion phenotype.…”

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confidence: 99%

Persistence of exhaustion in cured hep C

Kaplan

2017

Blood

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In this issue of Blood, Del Padre et al 1 evaluated the impact of eliminating chronic antigen exposure on B-cell exhaustion in the human therapeutic setting of directacting antiviral therapy for chronic hepatitis C virus infection (HCV) complicated by mixed cryoglobulinemia (MC). The phenotype of hepatitis C-related MC B cells has been previously demonstrated by this group and others 2 to include low-level CD21 expression (CD21 low ) and hypoproliferation in response to stimulation either through the B-cell receptor or Toll-like receptor 9, imperfectly termed "exhausted" or "anergic." At baseline, CD21 low B cells from HCVinfected patients expressed markers of chronic activation, with elevated and nearmaximal basal levels of phosphorylated extracellular signal-regulated kinase, and were also predisposed to apoptosis. During oral direct-acting antiviral therapy, the authors observed that by 4 weeks (at which point, most patients have no circulating HCV RNA), these basal abnormalities at least partially normalized. During longitudinal follow-up after patients were documented as cured, the overall frequency of CD21 low cells progressively declined from 50% to 30% of circulating B cells. However, the frequency of V H 1-69 1 B cells specific for HCVrelated MC generally remained stable, although some regained CD21 expression. Despite partial resolution of the exhaustion phenotype, surviving V H 1-69 1 B cells remained hypoproliferative upon Toll-like receptor 9 ligation, suggesting that the B-cell exhaustion phenotype is durably programmed into antigen-specific B cells during long-term extracellular antigen exposure. Mixed cryoglobulinemia is one of several B-cell proliferative disorders that may result from chronic hepatitis C infection, and it is thought to be driven by expansion of HCV envelope-specific B cells that preferentially use immunoglobulin gene segments V H 1-69 and V k [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]3 and to evolve rheumatoid factor activity through somatic hypermutation. 4Although MC is an infrequent complication of chronic hepatitis C infection, the technological ability to identify and isolate HCV-specific B cells via an anti-idiotype V H 1-69-specific antibody (G6) has made this condition an important model for studying humoral immune dysfunction during human chronic viral infection. Prior studies have identified that V H 1-69 1 B cells manifest genetic signatures of enhanced interferon-mediated responsiveness, apoptosis, and B-cell anergy; are phenotypically most commonly CD27

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T-bet+ B cells are induced by human viral infections and dominate the HIV gp140 response

Cited by 151 publications

References 78 publications

T-bet-expressing B cells during HIV and HCV infections

T-bet-expressing B cells during HIV and HCV infections

Signals that drive T-bet expression in B cells

Persistence of exhaustion in cured hep C

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