Case Reports

. 2022 Jul 22;7(73):eabq3277.

doi: 10.1126/sciimmunol.abq3277. Epub 2022 Jul 22.

Human T-bet governs the generation of a distinct subset of CD11c^highCD21^low B cells

Rui Yang^{1

2}, Danielle T Avery³, Katherine J L Jackson³, Masato Ogishi¹, Ibtihal Benhsaien^{4

5}, Likun Du⁶, Xiaofei Ye⁶, Jing Han¹, Jérémie Rosain^{7

8}, Jessica N Peel¹, Marie-Alexandra Alyanakian⁹, Bénédicte Neven¹⁰, Sarah Winter^{8

11}, Anne Puel^{1

7

8}, Bertrand Boisson^{1

7

8}, Kathryn J Payne³, Melanie Wong^{12

13}, Amanda J Russell³, Yoko Mizoguchi¹⁴, Satoshi Okada¹⁴, Gulbu Uzel¹⁵, Christopher C Goodnow^{3

16}, Sylvain Latour^{8

11}, Jalila El Bakkouri^{4

5}, Aziz Bousfiha^{4

5}, Kahn Preece¹⁷, Paul E Gray^{18

19}, Baerbel Keller^{20

21}, Klaus Warnatz^{20

21}, Stéphanie Boisson-Dupuis^{1

7

8}, Laurent Abel^{1

7

8}, Qiang Pan-Hammarström⁶, Jacinta Bustamante^{1

7

8

22}, Cindy S Ma^{3

16}, Jean-Laurent Casanova^{1

7

8

23

24}, Stuart G Tangye^{3

16}

Affiliations

¹ St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA.
² Department of Pediatrics, Weill Cornell Medicine, New York, NY 10065, USA.
³ Garvan Institute of Medical Research, Darlinghurst, NSW 2010 Australia.
⁴ Laboratory of Clinical Immunology, Inflammation, and Allergy, Faculty of Medicine and Pharmacy of Casablanca, King Hassan II University, 20460 Casablanca, Morocco.
⁵ Clinical Immunology Unit, Department of Pediatric Infectious Diseases, Children's Hospital, CHU Averroes, 20460 Casablanca, Morocco.
⁶ Department of Biosciences and Nutrition, Karolinska Institutet, 14183 Huddinge, Sweden.
⁷ Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, 75015 Paris, France.
⁸ Paris Cité University, Imagine Institute, 75015 Paris, France.
⁹ Immunology Laboratory, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris (AP-HP), 75015 Paris, France.
¹⁰ Department of Pediatric Immunology, Hematology, and Rheumatology, Necker Hospital for Sick Children, AP-HP, Paris, France.
¹¹ Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, INSERM UMR 1163, Imagine Institute, 75015 Paris, France.
¹² Children's Hospital at Westmead, Westmead, NSW, Australia.
¹³ Faculty of Medicine, University of Sydney, Sydney, NSW, Australia.
¹⁴ Department of Pediatrics, Hiroshima University, Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
¹⁵ Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
¹⁶ St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Darlinghurst, NSW 2010, Australia.
¹⁷ John Hunter Children's Hospital, Newcastle, NSW, Australia.
¹⁸ School of Women's and Children's Health, UNSW Sydney, Sydney, NSW, Australia.
¹⁹ Department of Immunology and Infectious Diseases, Sydney Children's Hospital, Sydney, NSW, Australia.
²⁰ Department of Rheumatology and Clinical Immunology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
²¹ Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
²² Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children, AP-HP, 75015 Paris, France.
²³ Howard Hughes Medical Institute, New York, NY 10065, USA.
²⁴ Department of Pediatrics, Necker Hospital for Sick Children, AP-HP, 75015 Paris, France.

PMID: 35867801
PMCID: PMC9413977
DOI: 10.1126/sciimmunol.abq3277

Case Reports

Human T-bet governs the generation of a distinct subset of CD11c^highCD21^low B cells

Rui Yang et al. Sci Immunol. 2022.

. 2022 Jul 22;7(73):eabq3277.

doi: 10.1126/sciimmunol.abq3277. Epub 2022 Jul 22.

Authors

Affiliations

¹ St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA.
² Department of Pediatrics, Weill Cornell Medicine, New York, NY 10065, USA.
³ Garvan Institute of Medical Research, Darlinghurst, NSW 2010 Australia.
⁴ Laboratory of Clinical Immunology, Inflammation, and Allergy, Faculty of Medicine and Pharmacy of Casablanca, King Hassan II University, 20460 Casablanca, Morocco.
⁵ Clinical Immunology Unit, Department of Pediatric Infectious Diseases, Children's Hospital, CHU Averroes, 20460 Casablanca, Morocco.
⁶ Department of Biosciences and Nutrition, Karolinska Institutet, 14183 Huddinge, Sweden.
⁷ Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, 75015 Paris, France.
⁸ Paris Cité University, Imagine Institute, 75015 Paris, France.
⁹ Immunology Laboratory, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris (AP-HP), 75015 Paris, France.
¹⁰ Department of Pediatric Immunology, Hematology, and Rheumatology, Necker Hospital for Sick Children, AP-HP, Paris, France.
¹¹ Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, INSERM UMR 1163, Imagine Institute, 75015 Paris, France.
¹² Children's Hospital at Westmead, Westmead, NSW, Australia.
¹³ Faculty of Medicine, University of Sydney, Sydney, NSW, Australia.
¹⁴ Department of Pediatrics, Hiroshima University, Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
¹⁵ Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
¹⁶ St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Darlinghurst, NSW 2010, Australia.
¹⁷ John Hunter Children's Hospital, Newcastle, NSW, Australia.
¹⁸ School of Women's and Children's Health, UNSW Sydney, Sydney, NSW, Australia.
¹⁹ Department of Immunology and Infectious Diseases, Sydney Children's Hospital, Sydney, NSW, Australia.
²⁰ Department of Rheumatology and Clinical Immunology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
²¹ Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
²² Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children, AP-HP, 75015 Paris, France.
²³ Howard Hughes Medical Institute, New York, NY 10065, USA.
²⁴ Department of Pediatrics, Necker Hospital for Sick Children, AP-HP, 75015 Paris, France.

PMID: 35867801
PMCID: PMC9413977
DOI: 10.1126/sciimmunol.abq3277

Abstract

High-level expression of the transcription factor T-bet characterizes a phenotypically distinct murine B cell population known as "age-associated B cells" (ABCs). T-bet-deficient mice have reduced ABCs and impaired humoral immunity. We describe a patient with inherited T-bet deficiency and largely normal humoral immunity including intact somatic hypermutation, affinity maturation and memory B cell formation in vivo, and B cell differentiation into Ig-producing plasmablasts in vitro. Nevertheless, the patient exhibited skewed class switching to IgG1, IgG4, and IgE, along with reduced IgG2, both in vivo and in vitro. Moreover, T-bet was required for the in vivo and in vitro development of a distinct subset of human B cells characterized by reduced expression of CD21 and the concomitantly high expression of CD19, CD20, CD11c, FCRL5, and T-bet, a phenotype that shares many features with murine ABCs. Mechanistically, human T-bet governed CD21^loCD11c^hi B cell differentiation by controlling the chromatin accessibility of lineage-defining genes in these cells: FAS, IL21R, SEC61B, DUSP4, DAPP1, SOX5, CD79B, and CXCR4. Thus, human T-bet is largely redundant for long-lived protective humoral immunity but is essential for the development of a distinct subset of human CD11c^hiCD21^lo B cells.

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Figures

**Figure 1.. *In vivo* development and *in vitro* function of B cells from a patient with inherited human T-bet deficiency.**
**(A)** Percentages of B cells among live lymphocytes gated from PBMCs of healthy donors (CTL), age-matched healthy donors (Age-CTL) or a patient (P or M/M) with inherited complete T-bet deficiency. **(B)** Percentages of naïve, memory and transitional B-cell subsets among B cells as in (A). **(C)** Percentages of IgG⁺ or IgA⁺ B cells among the memory B cells of CTL, age-matched CTL or P, measured by conventional flow cytometry (FACS). **(D)** Levels of total IgG, IgG1, IgG2, IgG3, IgG4, and IgE in plasma samples from P (M/M) and their normal range in the age-matched group (3 – 6 years of age). **(E)** Overview of the IGH repertoire for P (top row) and control donors aged 24 months (middle row) and 66 years (bottom row). Each column displays clones from a different isotype subclass. Each point is a B-cell clone, with point size scaled for clone size and colored according to the clone’s median SHM rate. Clones are positioned on the basis of V usage (x-axis) and CDR3 length (y-axis) with some jitter to prevent overplotting. **(F)** Points show the donor mean or median SHM for each IGH isotype, IGK and IGL repertoires; box plots summarize the median and interquartile ranges for all 6 donors. **(G)** Naïve B cells, isolated by FACS, from CTL or P were stimulated with CD40 ligand (CD40L) in the presence or absence of CpG₂₀₀₆ oligodeoxynucleotides (CpG) for 7 days. IgM levels in culture supernatants were determined by ELISA. **(H - J)** Naive B cells, as in (G), were stimulated with CD40L in the presence or absence of IL-21 for 7 days. Levels of IgM (H), IgG (I) or IgA (J) in culture supernatants were determined by ELISA. **(K - M)** Memory B cells, isolated by FACS, were stimulated with CD40L in the presence of CpG (K), IL-10 (L), and IL-21 (M) for 7 days. Levels of IgM, IgG and IgA in culture supernatants were determined by ELISA. (N and O) Memory B cells, isolated by FACS, were stimulated with CD40L in the presence IL-21. Levels of IgG1 (N), IgG2, IgG3, and IgG4 (O) in culture supernatants were determined by ELISA. **(P)** Memory B cells, isolated by FACS, were stimulated with CD40L in the presence or absence of IL-4 and IL-21. Levels of IgE in culture supernatants were determined by ELISA. In Fig. 1A, B, D, G - P bars represent the mean and the standard deviation. Dots represent individual samples for CTL or Age-CTL and technical replicates for M/M. Two-way ANOVA was used in (G – M and P). Mann-Whitney test was used in (N). Student t-test was used in (O). In (G - P), *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001, and ns = not significant (or not marked).

**Figure 2.. CD21^loCD11c⁺ B-cell levels are low in a patient with inherited T-bet deficiency.**
**(A)** PBMCs from 20 adult controls (CTL), four age-matched controls (Age-CTL), two IFN-γR1-deficient patients (IFN-γR1 ^−/−), P's healthy brother (WT/WT), heterozygous mother (WT/M), and P (M/M) were analyzed with a 29-color flow cytometry panel focusing on B cells. Surface staining of CD21 and CD11c on CD19⁺CD20⁺ B cells from different individuals, as indicated, is shown. CD21^loCD11c⁻ or CD21^loCD11c⁺ B cells were gated from CD19⁺CD20⁺ B cells, and their surface expression of CD19 and intracellular expression of T-bet were plotted. (B) Percentages of CD21^loCD11c⁻ and CD21^loCD11c⁺ B cells, as in (A), are shown. **(C)** Mean fluorescence intensity of T-bet of CD21^hiCD11c⁻, CD21^loCD11c⁻, and CD21^loCD11c⁺ B cells, as in (A), are shown. (D) PBMCs from 10 adult controls (CTL) and a patient with AR complete STAT1 deficiency (STAT1 ^−/−) were analyzed with the 29-color flow panel as in (A). Surface staining of CD21 and CD11c on CD19⁺CD20⁺ B cells from different individuals, as indicated. CD21^loCD11c⁻ or CD21^loCD11c⁺ B cells were gated from CD19⁺CD20⁺ B cells, and their surface expression of CD19 and intracellular expression of T-bet were plotted. (E) Percentages of CD21^loCD11c⁻ and CD21^loCD11c⁺ B cells, as in (D). (F) Mean fluorescence intensities (MFI) for CD11c expression on CD21^loCD11c⁺ B cells gated as in (D), from CTL or the STAT1 ^−/− patient. **(G - I)** The expression levels of CD19 (G), CD20 (H), and FcRL5 (I) on CD21^hiCD11c⁻, CD21^loCD11c⁻, CD21^loCD11c⁺T-bet^lo, and CD21^loCD11c⁺T-bet^hi B cells, as indicated by MFI. In Fig. 2B, C, and E - I, bars represent the mean and the standard deviation. Dots represent individual samples. One-way ANOVA test was performed for (B). Mann-Whitney tests were performed to compare CD21^loCD11c⁻, CD21^loCD11c⁺T-bet^lo, and CD21^hiCD11c⁻ B cells with CD21^loCD11c⁺T-bet^hi B cells (G - I). In (B, G - I), *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001, and ns = not significant (or not marked).

**Figure 3.. Depletion of some unique subsets of CD21lo B cells in the patient with inherited T-bet deficiency.**
**(A)** PBMCs from 30 healthy adults (CTL), four age-matched controls (Age-CTL), two IFN-γR1-deficient patients (IFN-γR1 ^−/−), P's healthy brother (WT/WT), P’s heterozygous mother (WT/M), and P (M/M) were analyzed with a 29-color flow cytometry panel focusing on B cells in two separate experiments. Batch correction was performed with the iMUBAC algorithm and FlowSOM unsupervised clustering was performed. These clusters from age-matched controls (Age-CTL), IFN-γR1-deficient patients (IFN-γR ^−/−), P (M/M), P's healthy brother (WT/WT), P’s mother (WT/M), and a STAT1-deficient patient (STAT1 ^−/−) are shown on UMAP graphs. Clusters increased or reduced in P are highlighted. **(B)** Frequency of cluster 25 among B cells. **(C - E)** Frequencies of clusters 9, 10, 13, 14, and combined among B cells. **(F)** PBMCs from P (M/M), adult controls (CTL), age-matched controls (Age-CTL) including P's healthy brother (WT/WT), and heterozygous mother (WT/M) were analyzed with a flow cytometry panel including IgM, IgG, IgA, IgD, and CD71 staining focusing on B cells. Their surface expression of IgM and IgG were plotted. **(G)** Surface expression of IgM and IgA, as in (F) were plotted. **(H – K)** Percentages of IgM⁺IgD⁺ (H), IgM⁻IgG⁺ (I), IgM⁻IgA⁺ (J), or T-bet⁺IgG⁺ (K) cells, as in (F), among indicated subsets of B cells were shown. CD21^loCD11c⁺ sub represents CD21^loCD11c⁺CD23⁻CD24⁻CD38⁻T-bet^hi B cells. In Fig. 3B - E, 3H - K, bars represent the mean and the standard deviation. Dots represent individual samples for CTL or Age-CTL and technical replicates for M/M. One-way ANOVA with multiple comparison tests were performed to compare CD21^hiCD11c⁻, CD21^loCD11c⁻, CD21^loCD11c⁺, and CD21^loCD11c⁺CD23⁻CD24⁻CD38⁻T-bet^hi (CD21^loCD11c⁺ sub) B cells against each other in (H – K). In (H - K), *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001, and ns = not significant (or not marked).

**Figure 4.. CITE-seq of CD21⁻ B cells from a patient with inherited human T-bet deficiency.**
**(A)** A schematic diagram of the experimental design. **(B)** PBMCs from the indicated individuals were labeled with hashtag Abs and oligonucleotide-conjugated anti-CD11c, anti-CD21, anti-CD95, anti-CXCR3, anti-FcRL5 Abs. CD3⁻CD56⁻CD20⁺CD21^lo B cells were isolated by FACS. **(C)** CD3⁻CD56⁻CD20⁺CD21⁻ B cells, as in (B), were subjected to CITE-seq. Cells from two Age-CTL, one IFN-γR1 ^−/− patient, and P, which had similar patterns of housekeeping gene expression, were subjected to dimensionality reduction by UMAP based on their transcriptome. **(D)** Four individual samples from the pool, as in (C), were split on the basis of their hashtags. **(E)** Frequencies of each cluster of CD21⁻ B cells from two Age-CTLs, one IFN-γR1 ^−/− patient, and P, as in (C and D). **(F)** Cells expressing CD11c surface protein detected by CITE-seq (ADT_CD11c), and cells expressing *ITGAX* or *TBX21* were highlighted in UMAP plots. **(G)** Cells expressing *ENC1*, *ITGB2*, and *TNFRSF1B* were highlighted in UMAP plots. **(H)** Protein levels for CD11c, CD21, CD95, CXCR3, and FcRL5, as determined by CITE-seq, grouped by transcriptome-defined clusters and sample groups. **(I)** Heat map showing the scaled expression levels of a selection of genes differentially regulated in cluster 3 B cells as in (C and D). In Fig. 4E, bars represent the mean and the standard deviation. Dots represent individual samples.

**Figure 5.. CSR and somatic hypermutation in T-bet-dependent CD.**
(A) Single-cell VDJ sequencing was performed jointly with CITE-seq. Frequencies of CD21^lo cells with more than one heavy or light chain are shown. (B) Frequencies of cells with more than one heavy or light chain within CD11c⁺ CD21^lo B cells (+) or CD11c⁻ CD21^lo (−) cells. (C) Frequencies of clonotypes common to at least 2 cells in each individual CD21^lo sample. (D) Frequencies of clonotypes common to at least 2 cells within CD11c⁺ CD21^lo B cells (+) or CD11c⁻ CD21^lo (−) cells. (E) Frequencies of cells that were unswitched or class-switched to IgE (IGHE), IgA1 (IGHA1) or IgA2 (IGHA2, combined as IgA1/2), IgG1 (IGHG1), IgG2 (IGHG2), IgG3 (IGHG3), or IgG4 (IGHG4) among CD21^lo cells. (F) Somatic hypermutation was analyzed as shown in this schematic diagram. Briefly, the numbers of mutations relative to the predicted germline sequence within a 280-nucleotide region (−21 to −300 bp from the start of CDR3 region) of each heavy and light chain were counted. The total number of mutations for both heavy and light chains for each given cell was divided by the total number of nucleotides counted, to calculate the mutation frequency. (G) Mutation frequency of each CD21^lo B cell from the indicated individuals. The frequencies of cells with mutation rates greater than 1% are highlighted. (H) Mutation frequency of each CD11c⁺ CD21^lo B cells (+) or CD11c⁻ CD21^lo (−) B cells from the indicated individuals. The frequencies of cells with mutation rates greater than 1% are highlighted. In Fig. 5A - E, bars represent values of each individual sample. In Fig. 5G and H, dots represent values for individual cells.

**Figure 6.. T-bet functions in a B cell-intrinsic manner to induce the generation of T-bet⁺ B cells *in vitro*.**
**(A)** Naïve B cells were purified from the peripheral blood of healthy donors (n=8) and cultured *in vitro* in medium alone (NS: non-stimulated), or with CpG₂₀₀₆, CpG₂₀₀₆ plus F(ab’)₂ fragments of goat anti-IgM/G/A Ab (CpG/aIg), CpG/aIg and IFN-γ (CpG/aIg/IFNγ), or CpG/aIg and IL-27 (CpG/aIg/IL-27). After 3.5 days, B cells were harvested, stained for the surface expression of CD19, CD95, CXCR3 FCRL5, and then for the intracellular expression of T-bet. Expression of T-bet and CD19 in B cells under indicated conditions from a healthy donor was plotted. Expression of T-bet, CD19, CXCR3, FCRL5, CD11c, and CD95 were shown. (**B - G**) Viable cells were then analyzed, to determine the level of expression (geometric mean fluorescence intensity [gMFI]) as in (A). The expression (gMFI) of (B) T-bet, (C) CD19, (D) FCRL5, (E) CD95 and (G) CXCR3 on CD19⁺T-bet⁺ B cells, and the proportions of T-bet⁺ B cells co-expressing CXCR3 (F) were also determined. (H) Naïve B cells purified from healthy donors or patients with pathogenic variants of *IFNGR1*, *IL27R*, *JAK1*, *IRAK4*, *STAT3* DN, *STAT1* (both AR and DN), or *TBX21* were cultured *in vitro* with anti-IgM/G/A Ab (CpG/aIg), CpG/aIg and IFN-γ (CpG/aIg/IFNγ), or CpG/aIg and IL-27 (CpG/aIg/IL-27) for 3.5 days. Expression of surface CXCR3 and intracellular expression of T-bet in B cells from indicated donors were plotted. (I and J) The proportions of CD19⁺T-bet⁺ B cells expressing (I) CXCR3 or (J) FCRL5 under anti-IgM/G/A Ab (CpG/aIg) or CpG/aIg and IFN-γ (CpG/aIg/IFNγ) conditions as in (H) were determined. **(K)** The proportions of CD19⁺T-bet⁺ B cells expressing CXCR3 under anti-IgM/G/A Ab (CpG/aIg) or CpG/aIg and IL-27 (CpG/aIg/IL-27) conditions as in (H) were determined. Fig. 6B - G, I - K show the mean ± standard error. Dots represent individual samples for CTL or Age-CTL and technical replicates for M/M. One-way ANOVA was used to compare each set of stimulation conditions with non-stimulated (NIL) conditions in (B – G). One-way ANOVA was used to compare control cells stimulated with anti-IgM/G/A Ab (CpG/aIg) with cells stimulated with CpG/aIg/IFNγ or CpG/aIg/IL-27 (I – K). *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001, and ns = not significant (or not marked). ND: not done

**Figure 7.. A unique epigenetic landscape determined by T-bet programs B-cell differentiation *in vitro*.**
(A) A heat map showing five loci at which chromatin accessibility differed between controls (CTL) and P (M/M) in the absence of stimulation and in response to aIg+CpG+IFN-γ and aIg+CpG+IL-27. (B) Chromatin accessibility of the *CCL3L1* and *CCL4L1* loci, at which the chromatin accessibilities of three regions differed between controls (CTL) and P (M/M) in the absence of stimulation and in response to aIg+CpG+IFN-γ and aIg+CpG+IL-27. (C) A heat map showing 902 T-bet-dependent loci, the chromatin accessibilities of which were differentially regulated in control cells, but not significantly different in the cells of P, in response to both aIg+CpG+IFN-γ and aIg+CpG+IL-27. **(D)** DNA motifs most significantly enriched in the 902 T-bet-dependent loci, the chromatin accessibilities of which were differentially regulated in control cells as in (C). (E and F) Chromatin accessibility of *FAS* (E) and *DUSP4* loci (F), that were differentially regulated in response to aIg+CpG+IFN-γ and aIg+CpG+IL-27 in control B cells but not in T-bet-deficient B cells. (G) A heat map showing a selection of 51 loci from the list, as in (C), the chromatin accessibilities of which were differentially regulated in control cells, but not in T-bet-deficient cells, in response to both aIg+CpG+IFN-γ and aIg+CpG+IL-27.

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References

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Human T-bet governs the generation of a distinct subset of CD11c^highCD21^low B cells

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Human T-bet governs the generation of a distinct subset of CD11c^highCD21^low B cells

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