EFB Dengue Literature Review

T-bet

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T-bet

Overview

T-bet (encoded by TBX21) is a T-box transcription factor originally identified as the master regulator of Th1 CD4⁺ T cell differentiation. In B cells, T-bet marks a cluster referred to by several overlapping (but non-identical) labels — age-associated B cells (ABCs), atypical B cells, or DN2 B cells — depending on disease context and the surface markers used; these labels intersect rather than coincide (see Atypical B Cell for the synonymy map). T-bet cooperates with ZEB2 to promote effector cell differentiation through inhibition of TCF7 (a TF critical for central memory fate), and its expression is induced by TLR7 signalling and IFN-γ.

Key Points from Literature

  • Highest expression in DN2 and aNAV cells: T-bet (TBX21) RNA and protein expression is highest in DN2 and aNAV cells, significantly above rNAV, SWM, DN1, and even PC (p<0.001 for all pairwise comparisons by flow cytometry MFI). DN2 and aNAV are the main depository of CD11c^hi T-bet^hi human B cells (see Jenks2018 - DN2 B Cells and EF Pathway in SLE, RNA-seq + flow cytometry n=4).

  • T-bet/ZEB2 cooperation: T-bet induces ZEB2, and the two cooperate to promote effector cell differentiation (analogous to their role in CD8⁺ T cell terminal differentiation, citing Dominguez et al. 2015). In DN2 cells, T-bet and ZEB2 are both highly expressed while TCF7 (the central memory TF they repress) is absent. DN1 and SWM cells express TCF7 but not T-bet, consistent with a central memory or GC-derived identity (see Jenks2018 - DN2 B Cells and EF Pathway in SLE).

  • T-bet induced by TLR7 + IFN-γ in vitro: rNAV cells stimulated with R848 + IFN-γ + IL-21 upregulate T-bet as they differentiate into aNAV and DN2 cells. In vitro-generated DN2 cells are CD23⁻ T-bet⁺ (see Jenks2018 - DN2 B Cells and EF Pathway in SLE).

  • Murine parallel: Murine CD11c^bright ABCs are T-bet-dependent and drive anti-viral IgG2a and lupus-like autoimmunity in a TLR7-mediated fashion. B cells expressing T-bet localise to the T-B cell border (extrafollicular zone) and drive autoimmunity (citing Rubtsova et al. 2017). SLE DN2 cells share this T-bet⁺ CD11c^bright phenotype (see Jenks2018 - DN2 B Cells and EF Pathway in SLE).

  • FOXO1 absent: FOXO1, a known T-bet repressor, is not expressed in DN2 or aNAV cells — releasing T-bet from transcriptional inhibition (see Jenks2018 - DN2 B Cells and EF Pathway in SLE).

  • T-bet is important but not absolutely required for ABC: CD11c⁺ B cells can be generated and maintained in the absence of T-bet. ABC markers including CD11c can be induced in vitro through diverse activation conditions without IFN-γ stimulation or T-bet expression. T-bet deficiency in humans confirms a central role but does not abolish all ABC (see Sanz2025 - Human Atypical B Cells Overview, review citing Yang et al. 2022, Du et al. 2019).

  • Autoregulatory TBX21 locus: The TBX21 locus contains an upstream distal element that is bound by T-bet itself, suggesting autoregulatory positive feedback. These features are present in both SLE and healthy DN2 cells (see Sanz2025 - Human Atypical B Cells Overview, review).

  • T-bet⁺/FcRL5⁺ vs. T-bet⁻/FcRL5⁻ memory partition: Within CD27⁺ memory, T-bet⁺/FcRL5⁺ memory ABC cells are poised for ASC differentiation and correlate with long-lived antibody responses. T-bet⁻/FcRL5⁻ canonical memory cells retain stem-like central memory properties (see Sanz2025 - Human Atypical B Cells Overview, review citing Nellore et al. 2023).

  • T-bet expression validated in acute COVID-19 by intracellular staining: Intracellular T-bet staining in ICU-C patients (n=4) confirmed that aN and DN2 cells express the highest T-bet levels (MFI) of any B cell subset — above rN, DN1, and DN3. This validates in an infection context the T-bet hierarchy previously established in SLE (see Woodruff2020 - EF B Cell Responses in COVID-19, spectral FCM + intracellular staining).

  • T-bet expression mapped on UMAP: T-bet expression overlaid on composite UMAP projections cleanly colocalised with the aN/DN2 region (cluster 2, ROI 1), distinguishing the EF pathway populations from naive, memory, and ASC clusters (see Woodruff2020 - EF B Cell Responses in COVID-19, Fig. 2e).

  • T-BET motifs are the top enriched motifs in DN2 accessible chromatin: ATAC-seq motif analysis showed T-BET binding motifs as the most enriched in DN2-specific DARs (vs. switched memory). T-BET, together with AP-1 and EGR, constituted the core DN2 motif signature — distinct from NF-κB, EBF, and OCT motifs enriched in switched memory (see Scharer2019 - Epigenetic Programming in SLE B Cells, ATAC-seq motif enrichment, n=9 SLE + n=12 HC).

  • T-BET chromatin programme is shared by HC and SLE DN2 cells — not disease-specific: The T-BET motif enrichment in DN2 accessible chromatin was present in both healthy controls and SLE, confirming that T-BET-driven programming is a normal feature of the DN2 differentiation state rather than an SLE-specific aberration. The disease-specific layer is AP-1/EGR amplification on top of the normal T-BET programme (see Scharer2019 - Epigenetic Programming in SLE B Cells).

  • T-BET autoregulatory loop confirmed by ChIP-seq: ENCODE ChIP-seq data showed T-BET binding at an upstream distal element of its own TBX21 locus, with enhanced chromatin accessibility at this element in both aN and DN2 cells. This confirms the autoregulatory positive feedback suggested by Sanz2025 (see Scharer2019 - Epigenetic Programming in SLE B Cells, ATAC-seq + ENCODE ChIP-seq from GM12878 B cells).

  • T-BET binding confirmed at key DN2 marker genes: T-BET ChIP-seq peaks mapped to accessible chromatin at GAS7, TNFRSF1B, ITGAX (CD11c), ZAP70, and TBX21 loci — all in regions specifically accessible in aN and DN2 cells (see Scharer2019 - Epigenetic Programming in SLE B Cells).

  • T-bet⁺ CD4⁺ T cell expansion in COVID-19 lymphoid tissue — TH1 skewing at the anatomical level: Multi-color immunofluorescence of post-mortem COVID-19 lymph nodes and spleens showed T-bet⁺ CD4⁺ T cells consistently increased in both organs, in both early and late disease. TH2 (GATA-3⁺) decreased; TH17 (RORγt⁺) variably increased. This TH1 skewing at the tissue level is consistent with the TNF-α-mediated GC TFH block — T-bet expression in CD4⁺ T cells is associated with IFN-γ and TNF-α production, which may suppress Bcl-6 expression required for GC-TFH differentiation (see Kaneko2020 - GC Loss and TFH Block in COVID-19, n=11 COVID + controls, multi-color immunofluorescence).

  • T-bet expected but not directly stained in acute dengue: CD21⁻CD11c⁺ B cells within the IgD⁻CD27⁻ gate are significantly expanded during acute dengue — a phenotype consistent with T-bet⁺ DN2 identity based on the Jenks2018, Woodruff2020, and Scharer2019 characterisations. However, T-bet was not directly stained in this study. Formal confirmation of T-bet expression on dengue EF B cells remains outstanding and is the single most important pending phenotypic validation (see Ansari2025 - Peripheral T Helper Subset Drives B Cell Response in Dengue, n=170 acute dengue, multi-color FCM without intracellular T-bet).

  • TBX21 (T-bet) defines the alternative B cell lineage at the transcriptomic level: scRNA-seq of >12,000 B cells placed TBX21 expression as one of three core genes (alongside ITGAX/CD11c and FCRL5) defining the alternative lineage. T-bet expression was consistent across all alternative lineage clusters (atBC1, atBC2, atBC3, MBC1) and absent from the classical lineage (MBC2, MBC3, actBC), confirming T-bet as a lineage-defining rather than activation-state marker in this framework (see Sutton2021 - Alternative Lineage B Cells in Vaccination and Infection, n=4, 10x Chromium scRNA-seq).

  • T-bet is the defining transcription factor of the ABC population — and IFN-γ is its primary inducer. ABCs were defined by T-bet from their first description (CD19⁺CD21⁻CD23⁻T-bet⁺CD11c⁺ in aged mice); in the ABC differentiation programme IFN-γ primarily promotes T-bet while IL-21 induces CD11c. In autoimmunity, elevated T-bet in B cells drives increased antibody production, antigen presentation, and even germinal-center formation (see Lamprinou2026 - ABCs and DN B Cells, opinion, citing Hao 2011 / Naradikian 2016 / Liu 2024 / Rubtsov 2017).

  • T-bet is the marker that separates DN2 from the other DN subsets. Among the DN subsets (DN1–DN4), DN2 is the only one that highly expresses T-bet; DN1 and DN4 are T-bet⁻ and DN3 is T-bet^low. T-bet is thus the single axis that aligns DN2 with the ABC/atypical cluster while excluding the CXCR5⁺ DN subsets (see Lamprinou2026 - ABCs and DN B Cells, opinion; Double-Negative B Cell).

  • Independent restatement that T-bet is dispensable — now from two further mouse conditional-KO primaries. CD11c⁺ ABCs arise in both infection and autoimmune models in the absence of T-bet; the review states plainly that although T-bet “was believed to be essential for ABC development,” recent findings “indicate that T-bet is not strictly needed” (see Glaros2025 - Multilayered Identity of B Cell Memory, review, citing Du 2019 Eur J Immunol + Levack 2020 J Immunol). This corroborates the Sanz2025 bullet above from a second review lineage and adds ZEB2 as the proposed shared driver imposing the ABC programme across contexts.

  • Murine T-bet⁺ MBC-like cells persist as tissue residents in a GC-absent infection. In Ehrlichia muris infection — where splenic GCs are absent — somatically hypermutated IgM⁺T-bet⁺ MBC-like cells are found resident in liver and spleen, generated GC-independently and persisting after clearance (see Glaros2025 - Multilayered Identity of B Cell Memory, review, mouse; Tissue-Resident Memory B Cell). T-bet⁺ B cells are therefore not exclusively a circulating, activation-state population.

  • T-bet as the master regulator of ABC differentiation, reproduced across labs and phenotyping schemes. T-bet is treated as the master transcription factor of the ABC population from its earliest description (CD19⁺CD21⁻CD23⁻T-bet⁺CD11c⁺ in aged mice), with IFN-γ as its primary inducer (IL-21 instead drives CD11c). The T-bet association reproduces regardless of whether the population is isolated by Hao’s CD21/CD23/CD95/CD43-negative criteria or by Rubtsov’s CD11c⁺ criteria — i.e., it is not an artefact of one lab’s phenotyping choice (see Cancro2020 - Age-Associated B Cells, review — no original data; mouse).

  • T-bet induction kinetics: within 12 h, before the first division. In the two-signal ABC differentiation system, T-bet expression begins within 12 hours of combined TLR7/9 + cytokine exposure — well before the first cell division — which is argued to be too fast for a purely epigenetic mechanism and more consistent with an immediate shift in signalling or metabolic state (see Cancro2020 - Age-Associated B Cells, review — no original data; mouse, in vitro).

  • ★ CD11c induction may be cytokine-direct, not T-bet-downstream — independent, earlier convergence with the Glaros2025 T-bet demotion. Transcriptional analysis of IFN-γ- or IL-21-treated WT versus T-bet-deficient B cells showed some ABC features are strongly T-bet-dependent, but others — notably CD11c expression — were largely a direct effect of each cytokine rather than a downstream target of T-bet. The in vivo picture is called “somewhat controversial” (T-bet necessary for CD11c induction in some systems, not others), attributed to differing routes of ABC formation (see Cancro2020 - Age-Associated B Cells, review — no original data; mouse, transcriptional array). This is convergent support for the wiki’s existing “T-bet is confirmatory, not defining” position — arriving five years before, and from a different direction than, Glaros2025 - Multilayered Identity of B Cell Memory’s citation of mouse conditional-KOs (Du 2019, Levack 2020). The evidence types differ and should not be conflated: Cancro’s is transcriptional/in vitro (a specific marker, CD11c, dissociates from T-bet at the expression level), while Glaros’s is genetic (the whole ABC cluster still forms when T-bet is deleted). Different experiments, same directional conclusion.

  • Heterogeneity within the CD21⁻CD23⁻ gate: only ~2/3 are T-bet⁺. Within the murine CD21⁻CD23⁻ splenic B cell pool, only ~two-thirds of cells are T-bet⁺, and among those, roughly half are CD11c⁺ — implying at least three populations sit inside a CD21⁻-only ABC gate, which therefore over-calls ABC by roughly 50% relative to a T-bet-confirmed count (see Cancro2020 - Age-Associated B Cells, review — no original data; mouse, splenic). Directly relevant to B Cell Panel Variant 1’s T-bet-as-confirmation design.

  • ⚠ RESOLVED [2026-09-04] — “T-bet represses Blimp-1” is contradicted in B cells by primary data, and its probable provenance is the T cell literature. Cancro wrote: “Few if any plasma cells express T-bet, and there is evidence that T-bet represses Blimp-1, suggesting that the formation of plasma cells from ABCs likely involves the loss of T-bet expression” (see Cancro2020 - Age-Associated B Cells, review — no original data), attaching no numbered reference — unusual for an Annual Reviews article. Stone2019 - T-bet Promotes ASC Differentiation by Limiting IFN-gamma Inflammation (mouse, Be1/Be2 co-culture + ATAC-seq) tested the relationship directly and found no repression: deleting Tbx21 left day-2 Prdm1 mRNA equivalent and Blimp-1-motif chromatin accessibility unchanged (ns, n=871 motif-containing DARs) — the same motif set that Th1 priming opens at p=3.8 × 10⁻⁹⁰. By day 4 Prdm1 is lower without T-bet, i.e. T-bet indirectly supports Blimp-1. Stone’s own citations for T-bet-dependent Blimp-1 modulation (Oestreich 2012, Xin 2016) are T cell papers — the most likely source of Cancro’s sentence. The first clause fares better than the second: see the T-bet⁺ ASC compartment gradient bullet below. See BLIMP-1 for the same resolution.

  • T-bet⁺ ABC / T-bet⁺ T cell tissue-residency parallel. Growing evidence indicates T-bet⁺ ABCs differ from T-bet⁻ B cells in recirculation and tissue-residency properties — “an intriguing parallel with T-bet-expressing T cells,” suggesting the T-bet programme may be partly generic to effector memory cells with restricted tissue residency rather than B-cell-specific (see Cancro2020 - Age-Associated B Cells, review — no original data; mouse).

  • Open question: interchange between T-bet⁺ ABC and T-bet⁻ Bmem pools. Explicitly listed as unresolved: whether there is appreciable interchange between the T-bet⁺ ABC pool and T-bet⁻ conventional memory B cell pools, alongside two other open progenitor–successor questions (whether unswitched/unmutated IgM⁺ ABCs are progenitors of switched/mutated ABCs, and whether CD11c⁺ ABCs are a differentiation state derived from CD11c⁻ ABCs) (see Cancro2020 - Age-Associated B Cells, review — no original data; mouse).

  • ★ A quantitative caution for T-bet gating, and a warning against T-bet as an identity marker. The review’s adapted flow data show that CXCR5⁻ switched memory and CD27⁺⁺CD38⁺⁺ plasma cells do express some T-bet — their MFI is merely “significantly lower” than DN2 and activated naive. T-bet positivity is therefore a continuum in blood, not a clean on/off gate, and a T-bet⁺ gate drawn low will pull in SWM and PC. The review’s conclusion is stronger still: “the limited use of either CD21, T-bet or CD11c expression is inadequate to identify ABC or other distinct human B cell populations”. In vitro, T-bet++ is induced together with CD11c++ and CD21ˡᵒ by TLR7 + IFN + IL-21 in naive, DN and memory starting populations alike (see Sanz2019 - Consistent Classification of Human B Cell Populations, review — no original data).

  • ★ What T-bet actually does in a B cell committing to ASC fate: it is permissive, not instructive. T-bet does not regulate the early expression or activity of any canonical plasma-cell TF — Prdm1/Blimp-1, Irf4, Xbp1, Pou2af1 — and does not repress the B-cell-identity factors (Pax5, Bcl6) whose removal ASC commitment requires. What it does instead is repress the IFN-γ-induced inflammatory gene programme (NF-κB, TLR, STAT/IRF), which if left running locks the cell in an activated effector state incompatible with terminal differentiation. The causal test is direct: adding an NF-κB activator (betulinic acid) or TLR7/9 ligands to wild-type Be1 cultures reproduced the Tbx21^−/−^ ASC defect without affecting proliferation (see Stone2019 - T-bet Promotes ASC Differentiation by Limiting IFN-gamma Inflammation, mouse, in vitro Be1/Be2 + ATAC-seq/RNA-seq, ≥2–4 independent experiments). The B cell repressome is largely its own: of 1,375 T-bet-repressed genes in Be1 cells only 155 are shared with the 275 in Th1 cells.

  • ★ The requirement is cytokine-context-dependent, not universal. In μMT bone-marrow chimeras, B-cell-intrinsic T-bet was required for flu-specific IgG, bone-marrow ASC and IgG2c responses after influenza, but Hp-specific IgG and IgG1 responses after Heligmosomoides polygyrus (IL-4-dominated Th2) were intact (see Stone2019 - T-bet Promotes ASC Differentiation by Limiting IFN-gamma Inflammation, mouse, n=3–6/group, 5 independent experiments). The authors’ position is that T-bet, unlike Blimp-1 or IRF4, “is not a master regulator of ASC development.” Directly relevant to the wiki’s “confirmatory, not defining” reconciliation below — and it adds a distinction that debate lacks: T-bet may be dispensable for forming a CD11c⁺ ABC (Du 2019 / Levack 2020 via Glaros2025 - Multilayered Identity of B Cell Memory) while still being required for that cell to produce ASC output in a type-1 environment. Necessity for formation and necessity for output are separate questions.

  • ★ T-bet expression across ASC compartments is an anatomical gradient, not a binary — and T-bet⁺ B cells are not GC-excluded. Using a Tbx21-ZsGreen reporter after influenza, T-bet was expressed by GC B cells, ASCs and memory B cells alike. At 60 dpi, splenic ASCs were 32.5 ± 19.4% reporter⁺ (vs 9.6 ± 2.5% of splenic B cells) whereas bone-marrow long-lived ASCs were only 0.87 ± 0.8% (vs 1.11 ± 0.7%) (see Stone2019 - T-bet Promotes ASC Differentiation by Limiting IFN-gamma Inflammation, mouse, reporter flow cytometry). This qualifies Cancro’s “few if any plasma cells express T-bet”: roughly right for the terminal bone-marrow compartment, wrong at the splenic ASC stage. It also supplies mouse primary data for the point Eisenbarth2025 - A Roadmap for Defining Extrafollicular B Cell Responses makes on consensus grounds — T-bet positivity is not evidence of GC-independence. Since the curator’s cohort reads blood only, a blood T-bet⁺ plasmablast’s compartment of origin is not determined by its T-bet status.

  • T-bet is required for memory B cell differentiation but not memory maintenance. Tamoxifen-induced deletion of Tbx21 from established day-90 flu memory B cells did not change memory B cell numbers over 10 days, but NP⁺ ASC recall after heterologous X31 challenge fell ~10-fold. CXCR3 expression dropped on total and NP⁺ memory B cells after deletion (T cell CXCR3 unaffected), confirming CXCR3 as a functional T-bet target in B cells (see Stone2019 - T-bet Promotes ASC Differentiation by Limiting IFN-gamma Inflammation, mouse, inducible Tbx21^fl/fl^hCD20-TAM-cre).

  • ★ IFN-γ is the obligate inducer of B cell T-bet, shown by omission rather than correlation. In the reconstructed cocktail essentially all naive B cells upregulated T-bet and IRF4; dropping anti-Ig, R848, IL-21, BAFF or IL-2 individually made little difference, but omitting IFN-γ left >80% of cells T-bet^neg/lo^ and also blocked IRF4 upregulation — “IFNγ signals are obligate for the in vitro generation of the T-bet^hi^IRF4^int^ B_DN_ pre-ASC like population” (see Zumaquero2019 - IFN-gamma Programs T-bet-hi B Cells for ASC Differentiation, human, n=20 HD + n=40 SLE + in vitro reconstruction). ATAC-seq at day 3 showed accessibility near T-bet motifs enriched specifically in IFN-γ-exposed cells (near STAT5 motifs in IL-2-exposed cells; greatest for both in the combined condition). This is the licensing half of the mechanism whose downstream half Stone2019 - T-bet Promotes ASC Differentiation by Limiting IFN-gamma Inflammation supplies in mouse — IFN-γ induces T-bet and opens the PC programme; T-bet itself then does not drive that programme but represses the inflammatory brake on it.

  • ★ The murine T-bet⁺CD11c⁺ population is generated by Tfh help delivered outside germinal centres, and its transcriptional identity is defined against GC B cells. Using a Tbx21-AmCyan reporter to gate B220⁺CD19⁺CD44^hi^CD11c⁺T-bet⁺ splenocytes, sorted-population RNA-seq at day 12 separated them from GC and naive follicular B cells by PCA: Itgax, Tbx21 and Fcrl5 were lower in GC B cells, while the GC signature genes Bcl6, S1pr2 and Aicda were downregulated in the T-bet⁺ population. Generation required CD4 help from Tfh, not Th1 — sorted Tfh transferred into infection-matched Tcrb⁻/⁻ mice induced the cells, sorted Th1 did not (see Song2022 - Tfh Outside Germinal Centers Drive T-bet CD11c B Cells, mouse, LCMV-Armstrong + influenza PR8, n=3–5 mice/group). ⚠ Entirely murine; no human validation in this study.

Contradictions & Debates

  • ★ Is T-bet definitional for the ABC/atypical cluster, or its dominant correlate? The wiki carries both positions and they cannot both be right as stated:

    • Definitional: “T-bet is the defining transcription factor of the ABC population” and “DN2 is the only DN subset that highly expresses T-bet” (see Lamprinou2026 - ABCs and DN B Cells, opinion); TBX21 is one of three lineage-defining genes for the alternative lineage (see Sutton2021 - Alternative Lineage B Cells in Vaccination and Infection, n=4 scRNA-seq).
    • Dispensable: CD11c⁺ ABCs can be generated and maintained without T-bet (see Sanz2025 - Human Atypical B Cells Overview, review citing Yang 2022 / Du 2019; independently restated in Glaros2025 - Multilayered Identity of B Cell Memory, review citing Du 2019 / Levack 2020, mouse conditional-KO). Independent, earlier convergence from a different evidence type: Cancro2020 - Age-Associated B Cells (2020, review — no original data; mouse, transcriptional array) found CD11c induction is largely a direct cytokine effect rather than a T-bet-downstream target — a transcriptional/in vitro dissociation of CD11c from T-bet, five years before the genetic (conditional-KO) demotion the wiki carries via Glaros2025.
    • Reconciliation: the evidence for “definitional” is descriptive (T-bet marks the cluster in human cross-sectional cohorts and transcriptomics), while the evidence for “dispensable” is genetic (the cluster still forms when T-bet is deleted). Both can hold: T-bet is a reliable marker of the dominant ABC state without being required to build one. The wiki should therefore treat T-bet as confirmatory, not defining, and keep CD11c as the primary axis — consistent with CITE-seq finding CD11c the best single surface marker (Sutton2021 - Alternative Lineage B Cells in Vaccination and Infection).
    • ★ Panel consequence (actionable). B Cell Panel Variant 1 Panel 4 adds intracellular T-bet specifically to confirm DN2/ABC identity in dengue — the wiki’s single most-wanted phenotypic validation (see the Ansari2025 bullet above). If a T-bet-independent CD11c⁺ fraction exists in human acute infection, a T-bet-gated definition undercounts it by an unknown margin. Recommended reporting: gate on CD11c/CD21 as primary and report T-bet⁺ as a fraction of the CD11c⁺ DN gate, rather than requiring T-bet positivity for the DN2 call. Tracked as a Watch Item.

  • ★ A third position that reframes the debate above: T-bet may report the cytokine environment rather than any pathway. The “definitional vs. dispensable” dispute recorded above treats T-bet as a property of the cell. The consensus Perspective argues it is substantially a property of the milieu: type 1 cytokines (IFN-γ, IL-12) and particular TLR signals drive B cell T-bet, “reflecting the nature of the immune environment but not necessarily a singular type of response.” Consistent with this, T-bet is expressed by GC B cells and by GC-derived memory B cells, not only by GC-independent effectors. The authors’ analogy is pointed: one would not conclude that all T-bet⁺ type 1 T cell subsets — Tfh1, Th1, CD8 — are the same population (see Eisenbarth2025 - A Roadmap for Defining Extrafollicular B Cell Responses, consensus Perspective, 12 authors, no primary data). This strengthens the wiki’s existing “confirmatory, not defining” reconciliation and adds a further restriction: T-bet positivity is not evidence of GC-independence. For a dengue cohort, in which acute infection produces a strongly type-1-skewed cytokine environment, T-bet⁺ B cells should be expected on environmental grounds alone, and their presence is not by itself a pathway readout. See GC-Independent Response.

DN2 B Cell, Age-Associated B Cell, Atypical B Cell, Activated Naive B Cell, ZEB2, Double-Negative B Cell, CD11c, TLR7, IL-21, Extrafollicular Response, FCRL5, CXCR3, ATF3, EGR, Peripheral Helper T Cell, GC-Independent Response

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