T-bet+ B cells are induced by human viral infections and dominate the HIV gp140 response
James J. Knox, Marcus Buggert, Lela Kardava, Kelly E. Seaton, Michael A. Eller, David H. Canaday, Merlin L. Robb, Mario A. Ostrowski, Steven G. Deeks, Mark K. Slifka, Georgia D. Tomaras, Susan Moir, M. Anthony Moody, Michael R. Betts
James J. Knox, Marcus Buggert, Lela Kardava, Kelly E. Seaton, Michael A. Eller, David H. Canaday, Merlin L. Robb, Mario A. Ostrowski, Steven G. Deeks, Mark K. Slifka, Georgia D. Tomaras, Susan Moir, M. Anthony Moody, Michael R. Betts
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Research Article AIDS/HIV Immunology

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

Abstract

Humoral immunity is critical for viral control, but the identity and mechanisms regulating human antiviral B cells are unclear. Here, we characterized human B cells expressing T-bet and analyzed their dynamics during viral infections. T-bet+ B cells demonstrated an activated phenotype, a distinct transcriptional profile, and were enriched for expression of the antiviral immunoglobulin isotypes IgG1 and IgG3. T-bet+ B cells expanded following yellow fever virus and vaccinia virus vaccinations and also during early acute HIV infection. Viremic HIV-infected individuals maintained a large T-bet+ B cell population during chronic infection that was associated with increased serum and cell-associated IgG1 and IgG3 expression. The HIV gp140–specific B cell response was dominated by T-bet–expressing memory B cells, and we observed a concomitant biasing of gp140-specific serum immunoglobulin to the IgG1 isotype. These findings suggest that T-bet induction promotes antiviral immunoglobulin isotype switching and development of a distinct T-bet+ B cell subset that is maintained by viremia and coordinates the HIV Env–specific humoral response.

Authors

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

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Figure 4

Transcriptional analyses of T-bethiCD85jhi cells and other B cell subsets in HIV-negative donors and during HIV infection.

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Transcriptional analyses of T-bethiCD85jhi cells and other B cell subset...
(A) Heatmap depicting relative RNA transcript expression levels for 91 targets (1 per row) in HIV-negative donors (n = 4). Each column represents a specific B cell subset (colored bars above and below heatmap) sorted from 1 donor. (B) t-Distributed stochastic neighbor embedding (tSNE) analysis of transcriptional relationships between sorted B cell subsets from 4 healthy donors. Each color represents a sorted B cell subset and clusters are highlighted with the corresponding color. (C) AICDA transcript expression (log2 units) of HIV-negative donors (gray; n = 4) and progressors (black; n = 5) per B cell subset. Trans., transitional; RM, resting memory; PB, plasmablast. Each data point represents transcript expression from 1 individual. Horizontal bars represent the mean ± SEM. Statistical comparison calculated using repeated-measures ANOVA with Tukey’s multiple comparisons. (D) Quantitative reverse transcription PCR of AICDA transcript in CD21–CD27– B cells of progressors transfected with control or T-bet siRNA. Values represent AICDA transcript level as a fraction of no-siRNA treatment condition. Statistical comparison calculated using paired t test. (E) Comparison of transcript expression levels for 91 gene targets between healthy donors (n = 4) and progressors (n = 5). Each data point represents the mean expression value calculated for HIV-negative donors (x value) and progressors (y value). Lines represent 90% prediction bands of calculated linear regression. Activation-induced cytidine deaminase (AICDA) transcript is depicted in red. *P ≥ 0.01 to < 0.05; **P ≥ 0.001 to < 0.01 (C and D).