EFB Dengue Literature Review

CD11c

14 min read

CD11c

Overview

CD11c (encoded by ITGAX) is an alpha integrin primarily expressed on dendritic cells and monocytes. On B cells, high CD11c surface expression marks extrafollicular plasmablasts, age-associated B cells (ABCs), and the DN2 B cell subset. CD11c is one of the defining markers of the DN2 phenotype (IgD⁻CD27⁻CXCR5⁻CD21⁻CD11c⁺) and is used to discriminate DN2 from DN1 cells.

Key Points from Literature

  • DN2 cells are CD11c bright: CD11c is highly expressed on DN2 cells and aNAV cells but low/absent on DN1, SWM, and rNAV. CD11c expression validated at both RNA (ITGAX) and protein level, with complete concordance (see Jenks2018 - DN2 B Cells and EF Pathway in SLE, RNA-seq + flow cytometry).

  • Gating utility: CXCR5 vs. CD11c dot plots on IgD⁻CD27⁻ cells cleanly separate DN1 (CXCR5⁺CD11c^lo) from DN2 (CXCR5⁻CD11c^hi). CD21 vs. CD11c provides equivalent discrimination (see Jenks2018 - DN2 B Cells and EF Pathway in SLE).

  • Shared with aNAV cells: aNAV cells (IgD⁺CD27⁻CXCR5⁻) are also CD11c bright — CD11c expression links these two populations phenotypically and transcriptionally (see Jenks2018 - DN2 B Cells and EF Pathway in SLE).

  • Murine parallel: Murine CD11c^bright ABCs are T-bet-dependent and important for anti-viral IgG2a responses and autoimmunity. Human DN2 cells share this CD11c^bright T-bet⁺ phenotype (see Jenks2018 - DN2 B Cells and EF Pathway in SLE, citing Rubtsova et al. 2015).

  • In vitro-generated DN2 cells upregulate CD11c: rNAV cells stimulated with TLR7 + IFN-γ + IL-21 upregulate CD11c as they differentiate into aNAV and DN2 cells, confirming that CD11c acquisition is part of the EF differentiation programme (see Jenks2018 - DN2 B Cells and EF Pathway in SLE).

  • CD11c is heterogeneous across B cell compartments: CD11c expression is not confined to DN2 cells — it is found on aNAV cells (highest), DN2, and at lower levels on a subset of CD27⁺ switched memory cells (activated ABC memory, both resting CD21⁺ and activated CD21lo fractions). Using CD11c alone to identify “ABC” or “AtB” therefore captures a heterogeneous mix of populations with different origins and functions (see Sanz2025 - Human Atypical B Cells Overview, review, Table 1 and Figure 2).

  • CD11c can be induced without T-bet or IFN-γ: CD11c and other ABC markers can be upregulated in vitro through diverse activation conditions in the absence of IFN-γ stimulation or T-bet expression. CD11c is therefore not a reliable proxy for T-bet⁺ identity (see Sanz2025 - Human Atypical B Cells Overview, review).

  • T-bet/FcRL5 can substitute for CD11c in gating: CXCR5 vs. CD11c, CXCR5 vs. T-bet, and CXCR5 vs. FcRL5 staining identify similar populations, providing practical flexibility for panel design (see Sanz2025 - Human Atypical B Cells Overview, review, Figure 2C).

  • CD11c expression validated in acute viral infection: In COVID-19, intracellular staining (n=4 ICU patients) confirmed that aN and DN2 cells had the highest T-bet and CD11c expression of any B cell population, above rN, DN1, and DN3. CD11c expression on UMAP projections cleanly demarcated the aN/DN2 region (ROI 1) that distinguished ICU from outpatient and healthy B cell profiles (see Woodruff2020 - EF B Cell Responses in COVID-19, spectral FCM + intracellular staining).

  • CD11c used in DN1/DN2/DN3 gating in 24-marker panel: The Woodruff2020 Table 1 gating scheme uses CD11c vs. CD21 within the DN gate to resolve DN1 (CD11c⁻CD21⁺), DN2 (CD11c⁺CD21⁻), and DN3 (CD11c⁻CD21⁻). This is the standardised gating applicable to spectral panels for EF pathway studies (see Woodruff2020 - EF B Cell Responses in COVID-19, Table 1).

  • CD11c⁺ marks EF B cells in acute dengue: CD21⁻CD11c⁺ B cells within the IgD⁻CD27⁻ (DN) gate are significantly expanded during acute dengue infection. This is the first demonstration of CD11c⁺ EF-phenotype B cells in dengue, validating the SLE/COVID-19 DN2 phenotype in a third disease context. CD11c was used alongside CD21 to identify EF B cells without CXCR5 staining (see Ansari2025 - Peripheral T Helper Subset Drives B Cell Response in Dengue, multi-color FCM, n=170 acute dengue).

  • CD11c is the best single surface marker for the alternative B cell lineage by CITE-seq: Combined transcriptome + surface protein measurement (CITE-seq) on >12,000 B cells showed that CD11c protein expression most cleanly identified the transcriptomically-defined alternative lineage (atBC1, atBC2, atBC3, MBC1), outperforming CD21⁻CD27⁻ gating which captured only 44.7% of atBC1 cells. This provides the strongest primary-source evidence that CD11c should replace or supplement CD21⁻CD27⁻ as the principal gating marker for this population (see Sutton2021 - Alternative Lineage B Cells in Vaccination and Infection, n=4, CITE-seq + 10x Chromium).

  • CD11c⁺ DCs interact with B cells at extrafollicular sites (murine precedent). In the foundational William2002 EF SHM study, CD11c⁺ dendritic cells were abundant within RF B cell clusters at the T zone–red pulp border and showed close physical interaction with Id⁺ B cells, in contrast to GCs where CD11c⁺ DCs are rare. This established CD11c⁺ DCs as a cellular component of the EF microenvironment, distinct from FDCs that define the GC niche. In the context of this wiki’s B cell focus, CD11c on B cells marks EF-pathway cells (DN2/aNAV), while CD11c on DCs marks the innate cellular partners at EF sites — both uses reflect the extrafollicular niche (see William2002 - Extrafollicular Somatic Hypermutation in Autoimmune Mice, IHC of splenic sections, MRL/lpr mice).

  • CD11c is the integrin that helped define the ABC, and IL-21 is its primary inducer. CD11c (with T-bet) was one of the two markers used to define age-associated B cells in aged mice; in the ABC/atypical differentiation programme IL-21 robustly induces CD11c whereas IFN-γ primarily drives T-bet — a clean division of labour between the two cytokines that cooperate (with TLR7/9) to generate the phenotype (see Lamprinou2026 - ABCs and DN B Cells, opinion, citing Hao 2011 / Naradikian 2016 / Liu 2024). This complements the wiki’s existing evidence that CD11c can also be induced without IFN-γ/T-bet (Sanz2025) — i.e., CD11c acquisition is cytokine-context-dependent.

  • ★ CD11c⁺ ABCs form without T-bet — CD11c is the more robust axis of the two. Although T-bet was long believed essential for ABC development, CD11c⁺ ABCs still arise in both infection and autoimmune models in the absence of T-bet, with ZEB2 proposed as the shared programme driver instead (see Glaros2025 - Multilayered Identity of B Cell Memory, review, no original data, citing Du 2019 Eur J Immunol + Levack 2020 J Immunol, mouse conditional-KO). This converges with the CITE-seq finding that CD11c is the best single surface marker for the alternative lineage (Sutton2021 - Alternative Lineage B Cells in Vaccination and Infection). Panel consequence: gate CD11c as primary and report T-bet as a fraction within it, rather than requiring T-bet positivity for the DN2/ABC call — see T-bet Contradictions and B Cell Panel Variant 1.

  • CD11c⁺ B cell depletion is therapeutic in autoimmunity but not risk-free. Depletion of CD11c⁺ or T-bet⁺ B cells decreased autoantibody levels and ameliorated disease in autoimmune models, with the review’s own caveat that such depletion also removes other activated B cell subsets. Countervailing evidence: in persistent Plasmodium infection, loss of the ZEB2-driven CD11c⁺ compartment reduced germinal-center B cells, indicating a supportive role for humoral immunity in infection (see Glaros2025 - Multilayered Identity of B Cell Memory, review). See ZEB2 Contradictions.

  • ★ CD11c induction may be a direct cytokine effect, not a T-bet-downstream event (F2) — and in vivo status remains controversial. Transcriptional analysis of IFN-γ- or IL-21-treated WT versus T-bet-deficient B cells found that while some ABC features depend strongly on T-bet, CD11c expression was largely a direct effect of each cytokine rather than a T-bet target. Cancro calls this “somewhat controversial” in vivo — T-bet has been shown necessary for CD11c induction in some systems but not others — and attributes the discrepancy to differing routes of ABC formation (see Cancro2020 - Age-Associated B Cells, review — no original data; mouse). This corroborates, from an independent mechanistic angle, the wiki’s existing position that CD11c is the more robust axis than T-bet.

  • CD11c was Rubtsov’s primary defining marker for the murine ABC. Of the two founding 2011 definitions, Hao et al. defined ABCs by loss of CD21/CD23/CD95/CD43, while Rubtsov et al. used CD11c⁺ expression on B220⁺CD19⁺ splenocytes as the primary criterion — the two schemes yield largely overlapping but non-identical populations (see Cancro2020 - Age-Associated B Cells, review — no original data; mouse).

  • Only about half of T-bet⁺ ABCs are CD11c⁺ (F4). Within the murine CD21⁻CD23⁻ splenic B cell pool, ~2/3 are T-bet⁺, and among those, roughly half are CD11c⁺ — so CD11c and T-bet identify overlapping but non-identical fractions of the ABC gate, and whether this reflects stable subsets or differentiation stages is unresolved (see Cancro2020 - Age-Associated B Cells, review — no original data; mouse, splenic).

  • ★ Open question: is CD11c⁺ a differentiation state derived from CD11c⁻ ABCs? Cancro lists this among the field’s unresolved progenitor–successor relationships. If CD11c⁺ status is a state rather than a stable compartment, a CD11c-gated frequency measures activation, not the size of the ABC pool — a direct consequence for any panel, including this wiki’s, that uses CD11c as the primary gating axis (see Cancro2020 - Age-Associated B Cells, review — no original data; mouse).

  • IgM⁺CD11c⁺ extrafollicular plasmablasts drive CD4-T-independent antibody responses in murine Ehrlichia infection. The Winslow group (Racine et al. 2008, J Immunol) described IgM⁺CD11c⁺ extrafollicular splenic plasmablasts responsible for this response, alongside protective, multipotential T-bet⁺ memory B cells (see Cancro2020 - Age-Associated B Cells, review — no original data; mouse).

  • CD11c⁺T-bet⁺ ABCs are required for anti-chromatin antibodies in the bm12 chronic-GVH SLE model — direct functional evidence that the CD11c⁺T-bet⁺ compartment contributes causally to autoantibody production in murine lupus, not merely correlates with it (see Cancro2020 - Age-Associated B Cells, review — no original data; mouse).

  • ★ [2026-08-27] CD11c is the second of the two axes defining the DN1–DN4 quadrant scheme, and it is what makes DN2 a blood finding. Within IgD⁻CD27⁻ cells, CD11c⁺ defines DN2 (CXCR5⁻) and DN4 (CXCR5⁺); CD11c⁻ defines DN1 (CXCR5⁺) and DN3 (CXCR5⁻). In inflamed tissue the CD11c⁺ subsets are the scarce ones — DN2 ~7 cells/mm² in COVID-19 lymph node against DN3’s ~400, and ~3% of the IgG4-RD salivary-gland DN pool. Whether that reflects genuine biology or loss of CD11c detectability in FFPE tissue is not addressed by the paper, and matters for interpreting any tissue CD11c stain (see Allard-Chamard2023 - DN3 B Cells Infiltrate Inflamed Tissues, n=38 blood + n=6–10 tissue).

  • [2026-08-27] CD11c was successfully detected in FFPE tissue by multiplex immunofluorescence (clone ab52632, Opal multiplex, TissueFAXS/TissueQuest with cut-offs set against positive controls), and was used to assign DN1–DN4 identity cell-by-cell in situ (Fig. 6C, S1B). This is a workable precedent for CD11c⁺ B cell detection in archival tissue — a route the wiki previously had no source for (see Allard-Chamard2023 - DN3 B Cells Infiltrate Inflamed Tissues, multi-colour IF). See Multi-color Immunofluorescence.

  • ★ The review that put CD11c on the DN map also says CD11c alone cannot identify these cells. Its Figure 2E shows CD11c highly expressed on SLE DN B cells, read as indicative of DN2 as activated effector cells and “very different from the proposed atypical memory B cells of HIV which are thought to be anergic” — the wiki’s earliest source for the effector-not-exhausted reading. But the same review concludes: “we postulate that the limited use of either CD21, T-bet or CD11c expression is inadequate to identify ABC or other distinct human B cell populations and that the present ABC assignment non-specifically integrates multiple B cell populations.” In vitro, TLR7 + IFN + IL-21 induces CD19++CD21ˡᵒ**CD11c++**T-bet++FcRL5⁺ in naive, DN and memory starting populations — i.e. the CD11c⁺ state is reachable from several parents (see Sanz2019 - Consistent Classification of Human B Cell Populations, review — no original data). This is the 2019 statement of the constraint Eisenbarth2025 - A Roadmap for Defining Extrafollicular B Cell Responses later made consensus.

  • [2026-08-29] CD11c is one of only two markers doing the subsetting work on the Emory lupus panel. Paired with CD21 it resolves DN1 (CD21⁺CD11c⁻), DN2 (CD21⁻CD11c⁺) and DN3 (CD21⁻CD11c⁻) within IgD⁻CD27⁻ cells, and the same CD21⁻CD11c⁺ combination defines activated naive cells inside the IgD⁺CD27⁻ gate. No T-bet, no CXCR5 and no FCRL5 appear anywhere in the paper’s own data — CD11c alone carries the activation axis in a 207-patient cohort (see Jenks2021 - B Cell Subset Composition in Cutaneous Lupus, n=207 + 46 HCD, cross-sectional, 8-marker conventional flow). This is the minimal-panel end of the range this wiki covers, and it is worth noting that a large clinically stratified result was obtained with it.

  • CD11c is induced as part of the IFN-γ-driven DN2 conversion, reaching near-saturation in vitro. The full cocktail drove >95% of naive B cells to an IgD⁻CD27⁻T-bet^hi^ phenotype that was CD11c⁺, and in SLE patient naive cultures 95% were CD11c⁺ at day 6. In patient blood, DN2 was defined as CD11c^hi^CXCR5^neg^ (79% of the B_DN_ gate) against DN1 CD11c^lo^CXCR5⁺ (17%) (see Zumaquero2019 - IFN-gamma Programs T-bet-hi B Cells for ASC Differentiation, human, n=20 HD + n=40 SLE + in vitro reconstruction). Supports CD11c as the primary DN2 axis while showing it is inducible by a defined cytokine set rather than lineage-fixed.

  • ★ A depletion caveat that invalidates the obvious experiment: CD11c-DTR cannot be used to delete CD11c⁺ B cells after viral challenge. The authors document that activated B cells increase DTR transgene expression independently of Itgax in vitro, and CD11c protein in vivo, so diphtheria toxin produced global ablation of proliferating B cells rather than selective loss of the CD11c⁺ subset; they restrict the system to memory-phase depletion (days 28/30) instead. In the same study Itgax is one of three genes — with Tbx21 and Fcrl5 — that are lower in GC B cells, i.e. CD11c tracks the GC-independent fate rather than the GC one (see Song2022 - Tfh Outside Germinal Centers Drive T-bet CD11c B Cells, mouse, LCMV-Armstrong, n=3–5 mice/group).

Contradictions & Debates

  • ★ CD11c positivity does not indicate a GC-independent origin — in either species. The wiki uses CD11c as the primary axis of the atypical/ABC cluster and, implicitly, as a marker of the extrafollicular pathway. A twelve-author consensus Perspective severs the second inference while leaving the first intact. In mice, CD11c⁺T-bet⁺ cells arise after viral infections as memory B cells derived from a primary GC reaction. In humans, CD11c⁺T-bet⁺FcRL5⁺ cells appearing within one week of influenza vaccination are CD27⁺CD21^lo with high SHM and hallmarks of prior GC selection and affinity maturation — recent GC emigrants, not EF products. Others are CD27⁺ reactivated memory. The verbatim conclusion: “CD11c and T-BET expression or lack of CD27 are not exclusive markers of EF B cell responses” (see Eisenbarth2025 - A Roadmap for Defining Extrafollicular B Cell Responses, consensus Perspective, 12 authors, no primary data). See GC-Independent Response.
  • CD11c^hi may be an activation state rather than a lineage identity. “Low expression of CD21 and CXCR5 and increased CD11c could indicate recent B cell activation rather than a permanent state of expression/lack of expression” (see Eisenbarth2025 - A Roadmap for Defining Extrafollicular B Cell Responses, consensus Perspective, 12 authors, no primary data). This does not undercut CD11c as the best single surface marker of the cluster (per CITE-seq in Sutton2021 - Alternative Lineage B Cells in Vaccination and Infection) — it undercuts reading a differentiation history off it. Practical consequence for the wiki’s dengue work: a CD11c⁺ expansion in acute dengue blood is real and countable, but calling it EF-derived requires evidence the panel cannot supply.

DN2 B Cell, Age-Associated B Cell, Atypical B Cell, Activated Naive B Cell, T-bet, IL-21, CXCR5, Double-Negative B Cell, Extrafollicular Response, FCRL5, CXCR3, CD21, Peripheral Helper T Cell, ZEB2, Tissue-Resident Memory B Cell, GC-Independent Response, DN3 B Cell

Sources

Graph View

Backlinks