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 2

Longitudinal T-bet+ B cell dynamics in yellow fever virus–vaccinated, vaccinia virus–vaccinated, or acutely HIV-infected individuals.

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Longitudinal T-bet+ B cell dynamics in yellow fever virus–vaccinated, va...
Longitudinal T-bet expression in memory B cells of (A) a yellow fever vaccinee and (B) a vaccinia vaccinee. Time of blood sampling after vaccination is depicted. (C) T-bet expression frequency in memory B cells of yellow fever vaccinees (n = 5 for all plots except E). Donor samples were binned to organize approximate weekly time points. (D) T-bethiCD85jhi cell frequency of total memory B cells in yellow fever vaccinees. (E) Ki67 expression frequency of T-bethiCD85jhi cells in yellow fever vaccines (n = 4). (F) T-bet median fluorescence intensity (MFI) of T-bethiCD85jhi cells (blue) and resting memory (RM) cells (black) in yellow fever vaccinees. No statistical differences were observed between RM time points. (G) T-bet expression in memory B cells of an acutely HIV-infected individual before infection and shortly after peak of viremia. (H) Memory B cell T-bet expression frequency from 7-donor cohort of acutely HIV-infected individuals at preinfection, acute, and chronic infection time points. Note that intracellular T-bet staining of early acute HIV samples in G and H was performed using a BD Cytofix/Cytoperm Kit. Statistical comparisons in C, D, E, F, and H calculated using repeated-measures 1-way ANOVA with Tukey’s multiple comparisons test. *P ≥ 0.01 to < 0.05; **P ≥ 0.001 to < 0.01.