Cutting Edge: B Cell–Intrinsic T-bet Expression Is Required To Control Chronic Viral Infection

Abstract

The role of antibody and B cells in preventing infection is established. In contrast, the role of B cell responses in containing chronic infections remains poorly understood. IgG2a (IgG1 in humans) can prevent acute infections and T-bet promotes IgG2a isotype switching. However, whether IgG2a and B cell-expressed T-bet influence the host-pathogen balance during persisting infections is unclear. Here we demonstrate that B cell specific loss of T-bet prevents control of persisting viral infection. T-bet in B cells not only controlled IgG2a production, but also mucosal localization, proliferation, glycosylation, and a broad transcriptional program. T-bet controlled a broad antiviral program in addition to IgG2a since T-bet in B cells was important even in the presence of virus-specific IgG2a. Our data supports a model in which T-bet is a universal controller of antiviral immunity across multiple immune lineages.

B cells expressing the transcription factor T-bet drive lupus-like autoimmunity

“…A novel subset of B cells named age-associated B cells (ABCs) has recently been identified by others and ourselves (7)(8)(9)(10). Unlike other B cells, ABCs express high levels of CD11c and the transcription factor T-bet.…”

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

“…The humoral immune system is critical for control of multiple viruses during both acute and chronic phases of infection (5,6), and most effective vaccines are thought to function by eliciting a protective humoral response (7). Humoral immunity is coordinated by memory B cells, antigen-specific subsets that can regulate the developing immune response via functions such as antigen presentation, cytokine Humoral immunity is critical for viral control, but the identity and mechanisms regulating human antiviral B cells are unclear.…”

“…Recent studies identified the immune cell-specific transcription factor T-bet as a critical regulator of murine antiviral B cell responses (6,19). T-bet was originally described as controlling CD4 + Th1 cell development and functionality (20), but T-bet also plays a role in B cell differentiation (21,22).…”

Persistence of exhaustion in cured hep C

“…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.…”

“…B-cell anergy, an adaptive response to chronic antigen exposure for autoreactive B cells, has been postulated to be a vulnerability exploited by pathogens to evade humoral sterilization and enhance permissiveness for chronic bloodborne infections. 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.…”