Many types of human CD21lo B cells identified in disease and healthy states
| Disease/tissue . | Defining phenotype . | Ig isotype . | SHM . | In vitro responses . | Disease correlates . | TFs . | Additional phenotypic markers . |
|---|---|---|---|---|---|---|---|
| CVID | CD21lo | Mostly IgM | Low (∼naïve) | ↓ proliferation ↑ Ig secretion | • Serum IFNγ, IFNγ-induced soluble factors (CXCL10) • cTfh1 cells | ↑ SOX4 TBX21 (T-bet) TOX | ↑ CD19 IgM CD95 CXCR3 CD22CD32 (FCGR2B) CD72 TNFRSF13B (TACI) ITGAX (CD11c) ITGB7 (CD49d) ↓ CD38 CD24 CD27 CXCR4CXCR5CCR7CD62L |
| Tissue-based MBC | FCRL4+CD27- | Mostly IgG, IgA | Similar to MBC | ↓ proliferation ↑ Ig secretion | NA | ↑ RUNX1 SOX5 | ↑ CD20 CXCR3 CD32 (FcRγIIB) CD80 CD86 CD11c CD95 RANKL CD40 CCR1 CCR5 CCR6 ↓ CD21 CD31 CXCR4 CXCR5 CCR7 |
| HIV | CD21loCD27− “Tissue-like/exhausted MBC” | IgG (G1, G3), IgA, some IgM | Intermediate between naïve and MBC | ↓ proliferation ↓ Ig secretion | • IFNγ-induced gene signature | ↑ T-bet, RUNX3 SOX5 TOX1 | ↑ FCRL4 CD72 CXCR3 CCR6 CD11c CD85j CD22 LAIR-1 TACI BCMA CD95 ↓ CXCR4 CXCR5 CD62L CCR7 BAFF-R |
| Malaria | CD21loCD27lo Atypical MBC | IgG > IgM | Similar to MBC Derived from MBC | ↓ proliferation ↓ Ig secretion | • Serum IFNγ | ↑ T-bet ↓BACH | ↑ FCRL5 CXCR3 CD11c CD85j CD19 CD20 CD22 FcγRIIb ↓ CD27 CXCR4 CXCR5 CD62L CCR7 |
| HCV | CD21lo | | Similar to MBC | ↓ proliferation | | ↑ SOX5 ZEB2 ↓BACH2 | ↑ CD11c FCRL4 CD19 CD20 CD22 CD72 CD95 |
| cHBV infection (including HBsAg-specific B cells) | CD21lo CD27± | Mostly unswitched | ND | ↓ Ca2+ flux, BCR signaling ↓ Ig secretion ↓ cytokine production ↑ apoptosis | • Low HBV-specific IgG | ↑ T-bet | ↑ CD11c CXCR3 FCRL5 CD22 BTLA PD1 FcγRIIb ↓ CXCR5 CD80 |
| SLE | •IgD−CD27− (DN) •Activated B cells • CD19hiCD20hi • CD11c+ • CD24−CD20hi | IgG | > naïve < MBC | ↑ autoAb secretion ↑ apoptosis | • Disease severity, serum autoAbs, renal involvement, lupus nephritis | ↑ T-bet ZEB2 BCL6 IRF4 Blimp1± XBP1 | • DN2: CXCR5neg CD19hi CD21lo CD11c+ • CD11c+: ↑ CD19 CD20, CD32 BAFF-R CD95 IL21R FCRL5 CD72 CXCR3 CCR9 SYK CD79B TLR9 CD80 CD86; TACIint, ↓ CXCR4 CXCR5 CCR7 • CD24−CD20hi: CD21lo CD11hi CD95hi CD27± SLAMF7hi; ↑ PDCD1 FCRL3 ILIRB1 ILIRB2 |
| Other AI (RA, SjS, GVHD, T1D) | CD21lo | IgM, IgG, IgA | Low (T1D) | ↓ proliferation | • Disease severity, autoAbs | ↑ T-bet SOX4 SOX5 TOX ZEB2 | ↑ CD19 CD22 CD86 CD58 CD11c CD72 CD32 CD85j CD85d Fas RANKL (RA) ITGAX FCRL5 ↓ CD40 BAFF-R IL-4R CCR7 CXCR4 CD44 CD62L CD27int |
| Trisomy 21 | CD11c+ | IgM, IgG, IgA | Reduced | Intact Ig secretion | • Inflammatory cytokines (IL-6) • cTfh1/17 cells • Circulating PCs | ↑ T-bet | ↑ CD86 CD95 CXCR3 CCR4 ↓ CD21 CXCR5 CCR7 |
| Cancer | scRNA-seq CD21−CD27− DN | | Low | ↓ BCR response ↓ plasmablast generation but autoAb secretion | • Poor outcomes • Worse response to ICI blockade in some cancers | ↑ TBX21 (T-bet) ZEB2 PRDM1IRF4XBP1TOXTOX2 ↓IRF8 | ↑ FCRL4 FCRL5 CD32A CD32B CD72 ITGAX (CD11c) PDCD1 (PD-1) CD80CD86 SYK TLR7 TLR9 DUSP4 CD85j LAIR1 ↓ CR2 (CD21) CD27 CD38 |
| Vaccine recall | CD21loCD27+ CD21loCD27−CD11c+CD21lo | | | ↓ Ig secretion | • Vaccine-specific IgG • cTfh1 cells | ↑ T-bet Blimp1 XBP1 | ↑ CD85j CD11c FCRL5 Ki67 CD80 CD95 BCMA ↓ CD38 CXCR4 CXCR5 |
| HDs | CD21loCD27- | FCRL5−: IgM, IgD FCRL5+: IgM, IgG | FCRL5−: low FCRL5+: increased but <MBCs | ↓ proliferation compared with naïve B, but FCRL5− > FCRL5+ ↑ apoptosis | | FCRL5+: ↑ TOX TOX2 TBX21 SOX5 BCL6 ↓ FOXP1 EGR1 | FCRL5-: CD32+ LAIR1+ PD1+ CCR7lo CD62Llo CXCR3hi CXCR4lo CXCR5lo BAFF-Rlo CD11cdim CD20++ CD86+ CD95+ TACIdim FCRL5+: CD22hi CD32hi LAIR1hi PD1hi CCR7lo CD62Llo CXCR3hi CXCR4neg CXCR5neg BAFF-Rlo CD11chi CD20++ CD86hi CD95hi TACI+ |
| Disease/tissue . | Defining phenotype . | Ig isotype . | SHM . | In vitro responses . | Disease correlates . | TFs . | Additional phenotypic markers . |
|---|---|---|---|---|---|---|---|
| CVID | CD21lo | Mostly IgM | Low (∼naïve) | ↓ proliferation ↑ Ig secretion | • Serum IFNγ, IFNγ-induced soluble factors (CXCL10) • cTfh1 cells | ↑ SOX4 TBX21 (T-bet) TOX | ↑ CD19 IgM CD95 CXCR3 CD22CD32 (FCGR2B) CD72 TNFRSF13B (TACI) ITGAX (CD11c) ITGB7 (CD49d) ↓ CD38 CD24 CD27 CXCR4CXCR5CCR7CD62L |
| Tissue-based MBC | FCRL4+CD27- | Mostly IgG, IgA | Similar to MBC | ↓ proliferation ↑ Ig secretion | NA | ↑ RUNX1 SOX5 | ↑ CD20 CXCR3 CD32 (FcRγIIB) CD80 CD86 CD11c CD95 RANKL CD40 CCR1 CCR5 CCR6 ↓ CD21 CD31 CXCR4 CXCR5 CCR7 |
| HIV | CD21loCD27− “Tissue-like/exhausted MBC” | IgG (G1, G3), IgA, some IgM | Intermediate between naïve and MBC | ↓ proliferation ↓ Ig secretion | • IFNγ-induced gene signature | ↑ T-bet, RUNX3 SOX5 TOX1 | ↑ FCRL4 CD72 CXCR3 CCR6 CD11c CD85j CD22 LAIR-1 TACI BCMA CD95 ↓ CXCR4 CXCR5 CD62L CCR7 BAFF-R |
| Malaria | CD21loCD27lo Atypical MBC | IgG > IgM | Similar to MBC Derived from MBC | ↓ proliferation ↓ Ig secretion | • Serum IFNγ | ↑ T-bet ↓BACH | ↑ FCRL5 CXCR3 CD11c CD85j CD19 CD20 CD22 FcγRIIb ↓ CD27 CXCR4 CXCR5 CD62L CCR7 |
| HCV | CD21lo | | Similar to MBC | ↓ proliferation | | ↑ SOX5 ZEB2 ↓BACH2 | ↑ CD11c FCRL4 CD19 CD20 CD22 CD72 CD95 |
| cHBV infection (including HBsAg-specific B cells) | CD21lo CD27± | Mostly unswitched | ND | ↓ Ca2+ flux, BCR signaling ↓ Ig secretion ↓ cytokine production ↑ apoptosis | • Low HBV-specific IgG | ↑ T-bet | ↑ CD11c CXCR3 FCRL5 CD22 BTLA PD1 FcγRIIb ↓ CXCR5 CD80 |
| SLE | •IgD−CD27− (DN) •Activated B cells • CD19hiCD20hi • CD11c+ • CD24−CD20hi | IgG | > naïve < MBC | ↑ autoAb secretion ↑ apoptosis | • Disease severity, serum autoAbs, renal involvement, lupus nephritis | ↑ T-bet ZEB2 BCL6 IRF4 Blimp1± XBP1 | • DN2: CXCR5neg CD19hi CD21lo CD11c+ • CD11c+: ↑ CD19 CD20, CD32 BAFF-R CD95 IL21R FCRL5 CD72 CXCR3 CCR9 SYK CD79B TLR9 CD80 CD86; TACIint, ↓ CXCR4 CXCR5 CCR7 • CD24−CD20hi: CD21lo CD11hi CD95hi CD27± SLAMF7hi; ↑ PDCD1 FCRL3 ILIRB1 ILIRB2 |
| Other AI (RA, SjS, GVHD, T1D) | CD21lo | IgM, IgG, IgA | Low (T1D) | ↓ proliferation | • Disease severity, autoAbs | ↑ T-bet SOX4 SOX5 TOX ZEB2 | ↑ CD19 CD22 CD86 CD58 CD11c CD72 CD32 CD85j CD85d Fas RANKL (RA) ITGAX FCRL5 ↓ CD40 BAFF-R IL-4R CCR7 CXCR4 CD44 CD62L CD27int |
| Trisomy 21 | CD11c+ | IgM, IgG, IgA | Reduced | Intact Ig secretion | • Inflammatory cytokines (IL-6) • cTfh1/17 cells • Circulating PCs | ↑ T-bet | ↑ CD86 CD95 CXCR3 CCR4 ↓ CD21 CXCR5 CCR7 |
| Cancer | scRNA-seq CD21−CD27− DN | | Low | ↓ BCR response ↓ plasmablast generation but autoAb secretion | • Poor outcomes • Worse response to ICI blockade in some cancers | ↑ TBX21 (T-bet) ZEB2 PRDM1IRF4XBP1TOXTOX2 ↓IRF8 | ↑ FCRL4 FCRL5 CD32A CD32B CD72 ITGAX (CD11c) PDCD1 (PD-1) CD80CD86 SYK TLR7 TLR9 DUSP4 CD85j LAIR1 ↓ CR2 (CD21) CD27 CD38 |
| Vaccine recall | CD21loCD27+ CD21loCD27−CD11c+CD21lo | | | ↓ Ig secretion | • Vaccine-specific IgG • cTfh1 cells | ↑ T-bet Blimp1 XBP1 | ↑ CD85j CD11c FCRL5 Ki67 CD80 CD95 BCMA ↓ CD38 CXCR4 CXCR5 |
| HDs | CD21loCD27- | FCRL5−: IgM, IgD FCRL5+: IgM, IgG | FCRL5−: low FCRL5+: increased but <MBCs | ↓ proliferation compared with naïve B, but FCRL5− > FCRL5+ ↑ apoptosis | | FCRL5+: ↑ TOX TOX2 TBX21 SOX5 BCL6 ↓ FOXP1 EGR1 | FCRL5-: CD32+ LAIR1+ PD1+ CCR7lo CD62Llo CXCR3hi CXCR4lo CXCR5lo BAFF-Rlo CD11cdim CD20++ CD86+ CD95+ TACIdim FCRL5+: CD22hi CD32hi LAIR1hi PD1hi CCR7lo CD62Llo CXCR3hi CXCR4neg CXCR5neg BAFF-Rlo CD11chi CD20++ CD86hi CD95hi TACI+ |
CVID, common variable immune deficiency; MBCs, memory B cells; cTfh cell, circulating T follicular helper cell; SLE, systemic lupus erythematosus; RA: rheumatoid arthritis; SjS: Sjogren’s syndrome; HBV, hepatitis B virus; HBsAg, hepatitis B surface Ag; HCV, hepatitis C virus; T1D, type 1 diabetes.