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 3

T-bet expression in B cells and antibody isotype repertoires during HIV infection.

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T-bet expression in B cells and antibody isotype repertoires during HIV ...
(A) T-bet expression in memory B cells of a representative HIV-negative donor and an HIV+ chronic progressor (progressor). (B) T-bet expression frequency of memory B cells in HIV-negative, progressor, HIV+ viremic controller (VC), HIV+ elite controller (EC), and HIV+ antiretroviral therapy–treated donors (ART); n = 10 donors per group. Statistical comparison calculated using 1-way ANOVA with Tukey’s multiple comparisons test. (C) Phenotype of T-bet+ B cell population from each cohort in B. Bars represent SEM. (D) T-bet median fluorescence intensity (MFI) of total T-bet+ cells from each cohort. Statistical comparison calculated using 1-way ANOVA with Tukey’s multiple comparisons test. (E) Frequency of IgG isotype–expressing B cells within total memory B cell compartment of HIV-negative individuals and progressors (HIV+) (n = 10 donors per group). Horizontal bars in B, D, and E represent the mean ± SEM. Statistics in E and F calculated using unpaired t test. (F) Absolute concentration of total serum antibodies by isotype from progressor (HIV+) and age/ethnicity–matched HIV-negative cohorts (n = 10 donors per group). (G) Correlations between T-bet expression frequency in memory B cells and serum antibody titers (ng/ml). Statistics calculated using Spearman correlation. *P ≥ 0.01 to < 0.05; **P ≥ 0.001 to < 0.01; ***P < 0.001.