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

Burton E. Barnett, Ryan P. Staupe, Pamela M. Odorizzi, Olesya Palko, Vesselin T. Tomov, Alison E. Mahan, Bronwyn Gunn, Diana Chen, Michael A. Paley, Galit Alter, Steven L. Reiner, Georg M. Lauer, John R. Teijaro and E. John Wherry
J Immunol August 15, 2016, 197 (4) 1017-1022; DOI: https://doi.org/10.4049/jimmunol.1500368

Abstract

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.

Introduction

Pathogens, such as HIV, hepatitis B virus, hepatitis C virus, Mycobacterium tuberculosis, and malaria, establish persistent infections despite ongoing T and B cell responses (1). These responses are often dysfunctional or exhausted and are unable to eradicate the pathogen. However, ongoing immune responses during chronic infections apply critical pressure on the pathogen to establish a host–pathogen equilibrium and, in some cases, contain the pathogen and limit or delay disease. Despite a clear role for T cells, it has become increasingly clear that humoral immunity is important during persistent viral infections (2). Indeed, despite the potent ability of HIV to evade Abs through escape mutations, naturally occurring broadly neutralizing Abs can develop in some individuals, and these Abs may help to contain chronic infection (2). However, precisely how ongoing B cell and Ab responses are involved in the outcome of chronic viral infections remains poorly understood.

To investigate B cell responses during ongoing persistent viral infection, we used lymphocytic choriomeningitis virus (LCMV) clone 13 (cl13) infection. LCMV cl13 causes viremia that is partially contained over time, with viral replication limited to some tissues after 2–3 mo. In contrast, acute infection with LCMV Armstrong (Arm) is rapidly cleared from all organs by days 8–10 postinfection (p.i.). Although Arm infection generates functional B and T cells, cl13 is associated with lymphocyte exhaustion (1, 3). Despite this exhaustion, T and B cells collaborate to hold cl13 replication in check long-term (1, 3). B cells are required for this viral containment because B cell–knockout (KO) mice or mice with an unrelated BCR transgene fail to control chronic infection (4, 5). However, the characteristics of Abs and B cells associated with viral containment during chronic infection remain poorly understood.

Materials and Methods

Mice and infections

All animals were housed at and used in accordance with protocols approved by the University of Pennsylvania Institutional Animal Care and Use Committee. Tbx21-flox, T-bet-GFP, CD19-cre, and pURF-Tg (i.e., IgG2a−/−) mice were described previously (6–8). Tbx21flox/flox and Tbx21flox/wt mice were crossed to CD19-cre mice. CD19-creTbx21wt/wt mice were used as wild-type (WT) controls. For acute infections, mice were infected i.p. with 2 × 105 PFU Arm, whereas for chronic infections, they were infected i.v. with 4 × 106 PFU cl13. Viral titers were measured as described (6).

Flow cytometry and cell sorting

Live/Dead Fixable Dead Cell Stain (Invitrogen) was used to identify live cells. Surface and intracellular staining and stimulation and cytokine staining were performed as described (6). Abs for flow cytometry were from eBioscience, BioLegend, BD Pharmingen, and Life Technologies. MHC tetramers were generated and used as described (6). Data were collected on a BD LSR II (BD Biosciences) and analyzed with FlowJo software (TreeStar, Ashland, OR). Cell sorting was done with a BD Aria II (BD Biosciences).

Serum and fecal Ab ELISAs

ELISAs were done using lysates of cl13-infected BHK cells. Serum ELISAs were done with serial dilutions starting at 1:100, whereas fecal ELISAs were done with serial dilutions of PBS/feces solution starting neat. Ab isotype detection was performed for IgM, IgG1, IgG2a, IgG2b, IgG3, and IgA using Abs from Southern Biotechnologies. Relative absorption is reported as log10, because values were normalized to account for dilution factors.

Gene expression microarray analysis

B cells for microarray were FACS sorted into TRIzol reagent and processed with QIAGEN RNeasy kits. RNA quality control was performed by spectrophotometry and gel analysis. B cell purity was >93% for each sample. Heat maps and gene lists were generated with the class neighbors function in GenePattern (false-discovery rate < 0.05). Gene set enrichment analysis (GSEA) was done via the Broad Institute (http://www.broadinstitute.org/gsea/index.jsp) using published gene sets for T-bet−/− CD8+ T cells (6). Microarray data were deposited in the Gene Expression Omnibus under accession number GSE81189 (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE81189).

Statistical analysis

The Student t test (paired and unpaired), Mann–Whitney tests, and log-rank tests were performed using Prism software (GraphPad, La Jolla, CA).

Results and Discussion

IgG2a (IgG1 in humans) is thought to be an effective antiviral isotype based on induction by acute infections and passive transfer where pathogen acquisition and/or acute infection is prevented (9, 10). However, it has remained unclear whether a causal relationship exists between IgG2a and the containment of ongoing chronic viral infections. The transcription factor T-bet has been implicated in IgG2a expression by B cells in noninfectious settings (11, 12). Therefore, we examined the role of T-bet in B cells and IgG2a in chronic LCMV infection. After cl13 or Arm infection, a population of T-bet+ B cells was induced by day 5 p.i. This population persisted after cl13 infection through day 30 p.i., whereas the number of T-bet+ B cells declined after Arm between days 14 and 30 p.i. (Fig. 1A). These T-bet+ B cells initially expressed markers of pre-germinal center (GC) B cells on day 5 p.i. and later acquired GC and memory B cell phenotypes (data not shown), consistent with previous data on T-bet expression in B cells after protein immunization (12).

FIGURE 1.
FIGURE 1.

B cell–expressed T-bet and antiviral IgG2a required for control of cl13 infection. (A) Flow cytometry of T-bet and IgM in splenic CD4−CD8−CD19+B220+IgD−CD138− B cells after Arm infection (upper panel). Number of T-bet+ B cells/spleen (lower panel). (B) B220+CD19+IgD−GL7−CD38+T-bet+ B cells in WT, T-betflox/wtCD19cre (conditional Het [cHet]), and T-betflox/floxCD19cre (conditional knockout [cKO]) mice at day 5 p.i. (spleen) (left panel); quantified data are also shown (right panel). (C) Viral titers in the blood of WT, cHet, and cKO mice (left panel) and in kidney at day 64 p.i. (middle panel). The frequency of mice in each group with detectable serum virus over time after cl13 infection (right panel). Log-rank score by survival statistics (score < 0.05 indicates a significant difference in time to clearance from the serum). (D) LCMV-specific serum IgG2a (i.e., IgG2c; called IgG2a throughout) in infected WT, cHet, cKO, and uninfected mice. (E) LCMV-specific serum IgM at day 7 p.i. (F) LCMV-specific IgG1, IgG2a, IgG2b, IgA, and IgG3 in the serum of infected mice at day 64 p.i. (left panel). Total serum IgG in serum of cl13-infected mice at day 64 p.i. (right panel). (G) IgG2a−/− mice and WT littermate controls were infected with cl13, and viral titers and IgG2a were measured at day 120 p.i. (H) cHet or cKO mice were infected with cl13, and cKO mice were treated i.p. at days 22, 27, and 32 p.i. with 200 μl of serum from WT mice at day 120 p.i. with cl13. Treated cKO, untreated cKO, and untreated cHet mice were analyzed for viral titers at day 35 p.i. in the serum (left panel) and kidneys (right panel). n = 4–7 mice per experiment, with each experiment repeated at least two times. *p < 0.05, **p < 0.01, ***p < 0.001

To examine the functional role of B cell–expressed T-bet during chronic viral infection, we bred Tbx21flox/flox mice (called T-betflox/flox hereafter) to Cd19cre/+mice to achieve B cell–specific deletion of T-bet. The immune compartments of naive T-betwt/wtCD19cre (WT), T-betflox/wtCD19cre (conditional Het [cHet]), and T-betflox/floxCD19cre (conditional knockout [cKO]) mice had normal numbers of mature B cells, conventional T cells, and regulatory T cells (data not shown). A robust T-bet+IgMlo B cell response was observed in WT mice after cl13 infection, but this response was almost completely absent in cKO mice and was substantially reduced in cHet mice (Fig. 1B). To test whether the absence of T-bet+ B cells had an impact on the outcome of chronic LCMV infection, we infected WT, cHet, and cKO mice with cl13. Serum viral titers rose to 104–105 PFU/ml by day 7 p.i. in all groups. Although WT mice contained viremia below detection by ∼day 45, cKO mice remained viremic until ≥8 wk, with viral titers remaining above 104 PFU/ml. cHet mice displayed an intermediate phenotype, with delayed control of viremia compared with WT mice (Fig. 1C). A similar effect on viral replication in tissues was also observed (Fig. 1C). Development of neutralizing Ab titers is delayed after cl13 infection. Although defective FcR function can impair viral control in some settings during cl13 infection (13, 14), nonneutralizing Abs may be important (9, 15, 16) (data not shown). Thus, nonneutralizing functions of T-bet–dependent Ab or B cell responses may play a role in chronic LCMV infection. In contrast to the importance of B cell–expressed T-bet in controlling cl13 infection, the resolution of acute Arm infection was unaffected by the absence of T-bet in B cells (data not shown).

High titers of LCMV-specific IgG2a were present by 3 wk p.i. in WT mice. In contrast, virus-specific IgG2a was nearly absent in cKO mice (Fig. 1D). Early antiviral IgM was implicated in the control of peak viremia during chronic LCMV infection (17). However, LCMV-specific IgM at day 7 p.i. was not different in T-bet WT and cKO mice (Fig. 1E). In addition, the amount of LCMV-specific serum IgG1, IgG2b, and IgG3 was not affected in the absence of T-bet in B cells, whereas serum IgA was reduced (Fig. 1F). This Ab-production defect was restricted to IgG2a, because the total amount of serum IgG was unaffected by the absence of T-bet (Fig. 1F). Interestingly, deletion of only one copy of T-bet in cHet mice had little impact on IgG2a (Fig. 1D); this is in contrast to the delay in viral control in these mice (Fig. 1C) and suggests that the effect of T-bet in B cells may be broader than only IgG2a class switching.

To directly test the importance of Ab in the T-bet KO phenotype, we performed two additional experiments. First, we examined viral control in mice with a specific deletion in IgG2a (8). Consistent with the above data, IgG2a-KO mice were unable to contain cl13 infection, supporting a key role for IgG2a (Fig. 1G). Next, we tested whether serum from WT mice containing LCMV-specific Ab, including IgG2a, could rescue the phenotype of T-bet cKO mice. Serum transfer only partially restored viral control in cKO mice (Fig. 1H). These observations are consistent with our data that cHet mice have delayed viral control, despite normal IgG2a levels, and suggest that T-bet controls aspects of B cell biology beyond IgG2a production.

Before the divergence in viral load (days 7–21 p.i.), virus-specific CD8+ and CD4+ T cell responses were similar among WT, cHet, and cKO mice (Supplemental Fig. 1). Moreover, T-bet+CD4+ T cells and the T-bethiPD1int and T-betintPD1hi subsets of CD8+ T cells (6) developed normally until later in infection, when major differences in viral load prevented comparison (data not shown). Normal antiviral CD8 and CD4 T cell responses were observed after Arm infection in cHet and cKO mice compared with WT mice (Supplemental Fig. 1). Although a deficiency in IgG2a+ B cells and production of serum IgG2a was also observed following Arm infection (Fig. 2), this had no detectable impact on clearance of acute infection. Thus, B cell–expressed T-bet plays a critical role in the control of chronic, but not acute, LCMV infection. Together, these data provoke the hypothesis that antiviral IgG2a is necessary, but not sufficient, to contain persistent viral infection and that IgG2a class switching is one of multiple mechanisms that rely on B cell–expressed T-bet.

FIGURE 2.
FIGURE 2.

B cell responses to acutely resolved LCMV Arm infection are largely normal in cHet and cKO mice. (A) Memory B cells from the spleens at day 30 p.i. with Arm were analyzed for expression of IgG2a and IgG1. (B) Serum LCMV-specific IgG2a and IgM were quantified over time after Arm infection. n = 2–6 mice per group. *p < 0.05.

We next examined B cell differentiation in WT, cHet, and cKO mice after cl13 infection. GC B cells were generated p.i. in cHet and cKO mice, as were memory B cells, with no obvious alterations in GC or memory B cell numbers or frequency at time points before viral loads diverged (Fig. 3A). Despite an increase in GC B cells at day 64 p.i. in cHet and cKO mice, when viral load was higher in these mice (Fig. 3B), the frequencies of IgG2a+ cells were substantially reduced in a gene dose–dependent manner, whereas IgG1+ memory B cells were present in normal frequencies (Fig. 3C). At day 8 p.i. with cl13, there was no difference in the frequency or total number of LCMV-specific CD4+ or CD8+ T cells in the spleens of WT and cKO mice (Supplemental Fig. 1, data not shown). Furthermore, T cell production of IFN-γ, IL-2, and TNF-α was largely unchanged between WT and T-bet cKO mice (Supplemental Fig. 1, data not shown). Finally, T follicular helper cells were formed normally in the absence of T-bet in B cells (Supplemental Fig. 1). These data suggest that the effects seen in cKO mice were not due to alterations in the T cell compartment. Because initial GC reactions and B cell differentiation occurred normally in T-bet cKO mice p.i., we investigated other aspects of B cell biology that might contribute to impaired viral immunity.

FIGURE 3.
FIGURE 3.

GC and memory B cell populations in T-bet–deficient B cells after cl13 infection. (A) GC B cells (CD4−CD8−NK1.1−B220+CD19+IgD−GL7+CD38+) were analyzed in spleens of cl13-infected mice at day 18 p.i. (B) GC (GL7+CD38−) and memory B cells (GL7−CD38+) were examined at day 64 p.i. (C) Memory B cells at day 64 p.i. were analyzed for expression of IgG2a and IgG1. n = 3–5 mice per experiment, with each experiment repeated at least two times. *p < 0.05, **p < 0.01.

Our data in cHet mice and serum-transfer experiments suggested that the role of B cell–expressed T-bet may extend beyond IgG2a (Fig. 1). To further interrogate the role of T-bet in antiviral B cell responses, we examined genome-wide transcriptional profiles of naive B cells and T-bet+ and T-bet− memory phenotype B cells at day 10 p.i. with cl13, prior to the divergence of viral loads (Fig. 1C), using T-bet–GFP reporter mice (7). Examination of key lymphocyte-lineage genes confirmed the isolation of B cells and absence of other lineage markers in purified T-bet+ and T-bet− memory phenotype B cells (Supplemental Fig. 1). T-bet+ and T-bet− memory phenotype B cells differentially expressed genes involved in cell migration (e.g., Cxcr3), differentiation and costimulation (e.g., Cd80, Ctla4, Fas), Ab diversification and mutation (Aicda), and proliferation, as well as γ-chain cytokine receptors (Il2ra, Il7r) and the glycosyltransferases (B4Galt1, Fut8, and Fut11) (Fig. 4A). In particular, these enzymes may be important given their role in Ab glycosylation and function (18). These data suggest that, in B cells, T-bet can control multiple key immune functions, including anatomical localization and expression of glycosylation enzymes, properties that likely influence the effectiveness of B cell and Ab responses in vivo.

FIGURE 4.
FIGURE 4.

T-bet controls a broad antiviral gene-expression program, including genes involved in migration, proliferation, and Ab glycosylation. CD3−NK1.1−CD19+B220+ were sorted as IgD+CD38+, IgD−IgM−T-bet+, and IgD−IgM−T-bet− B cells from cl13-infected T-bet–GFP reporter mice at day 10 p.i. (A) Selected genes differentially expressed between T-bet+ and T-bet− B cells, row normalized. (B) Genes significantly upregulated in T-bet+ B cells were compared with a microarray of T-bet+/+ versus T-bet−/− CD8+ T cells by GSEA. (C) Selected genes were confirmed by flow cytometry (upper panels); the mean fluorescence intensity (MFI) was quantified for each selected target (lower panels). (D) CD3−CD4−CD8−CD11c−NK1.1−Ter119−CD45.2+B220+CD19+IgD−CD138−GL7−CD38+ memory B cells were analyzed in the spleens, Peyer’s patches, lamina propria (LP), and intestinal epithelial lymphocyte compartment (IEL) of infected mice at day 10 p.i. (upper panels). Memory B cells were analyzed for expression of T-bet and IgM, and the frequency of T-bet+IgM− cells was quantified (lower panels). (E) IgD− memory B cells were quantified in WT and cKO mice in the spleen, Peyer’s patches, LP, and IEL (upper panels). The same cells were examined for the frequency of IgM−T-bet+ cells (lower panels). n = 2–5 mice per experiment, with each experiment repeated at least two times. ***p < 0.001.

GSEA revealed enrichment of the gene-expression signature of T-bet+ B cells in WT mice compared with T-bet−/− CD8+ T cells responding to Arm infection (Fig. 4B), suggesting that at least some of the transcriptional program regulated by T-bet is conserved between these two lymphocyte lineages. The genes that drove this enrichment included transcription factors, cell surface receptors, adhesion molecules, and cell cycle regulators (Supplemental Table I). T-bet controls antiviral gene programs in CD4 and CD8 T cells, NK cells, and group 1 innate lymphoid cells (19). The identification of a T-bet–dependent antiviral program in B cells now suggests that T-bet controls a conserved lymphocyte viral immunity module, although there are likely lineage-specific targets of T-bet in each case.

In agreement with the transcriptional profiles, T-bet+ memory phenotype B cells expressed high CXCR3, CD80, and Fas protein compared with T-bet− memory phenotype B cells (Fig. 4A, 4C). Furthermore, the Ab clones GL7 and 1B11 (CD43), which bind specific glycosylation changes, stained T-bet+ B cells more brightly than naive and T-bet− B cells, suggesting that glycosylation enzymes, such as B4Galt1, Fut8, and Fut11, are differentially regulated by T-bet (Fig. 4A, 4C).

To better understand the potential role of T-bet–dependent genes in cell migration, we examined the anatomical location of activated B cells following infection. T-bet+ memory phenotype B cells were highly enriched in the small intestinal mucosa, a peripheral site of inflammation and infection during cl13 infection (20), consistent with the upregulation of CXCR3 in T-bet+ B cells (Fig. 4A, 4C, 4D). Intraepithelial lymphocytes were especially enriched in T-bet+ memory phenotype B cells, with >65% of B cells in this compartment exhibiting a T-bet+IgM− phenotype (Fig. 4D). Consistent with a role for T-bet in regulating the quality and type of Ab-producing cells in the intestinal mucosa, we observed an increase in LCMV-specific IgA in the feces of cKO mice compared with WT mice (Supplemental Fig. 1). We hypothesized that B cell numbers in the gut would be reduced in T-bet cKO mice. Surprisingly, the total number of memory B cells at day 10 p.i. was equivalent in the intestinal mucosa of WT and cKO mice (Fig. 4E, upper panels). Therefore, we stained these B cells for T-bet. As shown above, the frequency of T-bet+ memory B cells was greatly reduced in the spleens of cKO mice. However, this difference was partially mitigated in the Peyer’s patches and was completely abrogated in the lamina propria lymphocyte and intestinal epithelial lymphocyte compartments (IEL) of cKO mice. Nearly all B cells present at these mucosal sites were T-bet+ escapees in the cKO mice (Fig. 4E, lower panels). These data indicate selective pressure for T-bet in migration to the intestine. These data suggest that B cell–intrinsic T-bet may regulate an important balance between systemic and mucosal Ab responses.

Together, our data suggest that T-bet+ B cells may be an important component of ongoing immune responses during chronic viral infections, even when neutralizing Ab is not a major factor. These data point to possible therapeutic opportunities to treat and/or prevent chronic infections through modulation of T-bet in B cells, further emphasizing the importance of understanding the in vivo mechanisms that drive T-bet+ B cell responses. The accompanying study delineates the cytokine regulation of T-bet expression in B cells (21). It will be interesting to test whether specific adjuvants or vaccine modalities enhance B cell–expressed T-bet and whether such approaches improve the isotype profile of Ab responses, change the functional quality of these Abs, and/or increase the rate of somatic hypermutation. Further, these studies support a model in which T-bet is a central regulator of antiviral immunity in all lymphocyte lineages. Future studies interrogating the transcriptional mechanisms of T-bet control of antiviral B cell responses should shed light on the extent of the core, conserved T-bet antiviral module.

Disclosures

The authors have no financial conflicts of interest.

Footnotes

  • This work was supported by National Institutes of Health Grants 1R56AI104898-01A1 (to J.T.), AI061699 (to S.L.R.), AI112521, AI105343, AI083022, and AI095608 (to E.J.W.), and AI082630 (to E.J.W. and G.M.L.).

  • The sequences presented in this article have been submitted to the National Center for Biotechnology Information Gene Expression Omnibus under accession number GSE81189.

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article:

    Arm
    Armstrong
    cHET
    conditional Het, T-betflox/wtCD19cre
    cKO
    conditional KO, T-betflox/floxCD19cre
    cl13
    clone 13
    GC
    germinal center
    GSEA
    gene set enrichment analysis
    IEL
    intestinal epithelial lymphocyte compartment
    KO
    knockout
    LCMV
    lymphocytic choriomeningitis virus
    p.i.
    postinfection
    WT
    wild-type.

  • Received July 7, 2015.
  • Accepted May 18, 2016.

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