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The role of Ab 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. We demonstrate that B cell-specific loss of T-bet prevents control of persisting viral infection. T-bet in B cells controlled IgG2a production, as well as mucosal localization, proliferation, glycosylation, and a broad transcriptional program. T-bet controlled a broad antiviral program in addition to IgG2a because T-bet in B cells was important, even in the presence of virus-specific IgG2a. Our data support a model in which T-bet is a universal controller of antiviral immunity across multiple immune lineages., (Copyright © 2016 by The American Association of Immunologists, Inc.)

Objective: To define the impact of chronic viremia and associated immune activation on B-cell exhaustion in HIV infection., Design: Progressive HIV infection is marked by B-cell anergy and exhaustion coupled with dramatic hypergammaglobulinemia. Although both upregulation of CD95 and loss of CD21 have been used as markers of infection-associated B-cell dysfunction, little is known regarding the specific profiles of dysfunctional B cells and whether persistent viral replication and its associated immune activation play a central role in driving B-cell dysfunction., Methods: Multiparameter flow cytometry was used to define the profile of dysfunctional B cells. The changes in the expression of CD21 and CD95 were tracked on B-cell subpopulations in patients with differential control of viral replication., Results: : Although the emergence of exhausted, CD21 tissue-like memory B cells followed similar patterns in both progressors and controllers, the frequency of CD21 activated memory B cells was lower in spontaneous controllers., Conclusion: Our results suggest that the loss of CD21 and the upregulation of CD95 occur as separate events during the development of B-cell dysfunction. The loss of CD21 is a marker of B-cell exhaustion induced in the absence of appreciable viral replication, whereas the upregulation of CD95 is tightly linked to persistent viral replication and its associated immune activation. Thus, these dysfunctional profiles potentially represent two functionally distinct states within the B-cell compartment.