In the immune system, B cells can be regarded as the "arsenal" for antibody production. Starting from hematopoietic precursor cells, they undergo differentiation and maturation along a defined pathway, with each stage carrying its own molecular markers, much like stage specific identity badges. The mouse model is a commonly used tool in B cell research, yet the developmental pathways and marker expression profiles of human and mouse B cells harbor species differences that cannot be ignored.
This article systematically reviews the complete developmental journey of B cells from progenitor cells to mature cells, with emphasis on comparing the similarities and differences in core markers across developmental stages between humans and mice. It integrates frontier hotspots and the latest research advances in immunology, clarifies the respective applicable scenarios and research challenges of human and mouse models, and summarizes key knowledge on B cell development, thereby providing a reference for study design and experimental scheme construction.
Table of contents
1. Introduction: why B cell development deserves a revisit
2. Molecular and phenotypic events across B cell developmental stages
3. Systematic comparison of marker differences between humans and mice
4. Current research hotspots and latest advances in B cell research
01 Introduction: why B cell development deserves a revisit
The value of research on B cell development has been redefined during 2023 to 2026 for three reasons.
(1) The developmental stages of B cells are themselves disease targets. In patients with immune thrombocytopenia (ITP), bone marrow and peripheral B cells show shortened V–J genomic distances at the IGK locus and reduced RAG expression in immature B cells, which points to insufficient receptor editing and further leads to an increased frequency of autoreactive and polyreactive naive B cells. In animal experiments, a causal link has been established between defective receptor editing and the generation of antiplatelet antibodies, identifying the immature B cell stage as a critical window of tolerance dysregulation. Similarly, in individuals with loss of function of human CBL (Casitas B-lineage lymphoma), B cells deviate at the immature developmental stage, with transitional B cells increased approximately tenfold, enhanced survival of autoreactive clones, and impaired memory B cell formation, class switching, and somatic hypermutation.
(2) Developmental lineages are more complex than the classical linear model. Among early B cell precursors, there exist differentiation states defined by new markers such as Ly6D, GFRA2, and BST1. B cell commitment may occur earlier than the traditional "pre-pro-B" stage, and parallel pathways that bypass this stage may even exist. This phenomenon corroborates the "marker expression asynchrony" and continuum features observed in immunophenotypic analyses of human B cell precursors (BCPs).
(3) Marker definitions directly impact clinical and translational research. B cell targeted therapies (anti CD20, BTK inhibitors, CD19/BCMA CAR-T) depend on accurate definition of the target population, while the classification of human B cells and plasma cells has long suffered from three problems: marker overlap, unclear population boundaries, and "mouse to human cross species extrapolation."
02 Molecular and phenotypic events across B cell developmental stages
B cell development comprises two major phases: central development completed within the bone marrow, and maturation in peripheral immune organs. The overall differentiation pathway proceeds as follows: progenitor cells → precursor cells → immature cells → mature naive B cells → activated memory B cells/plasma cells. The entire process involves tightly regulated gene rearrangement, positive selection, and negative selection to ensure that subsequent immune responses possess specificity and safety.
Early B cell development in mice has two naming systems: the Basel nomenclature (Rolink team) and the Philadelphia Hardy fractions, and the two systems cannot be fully mapped onto each other. In particular, the Basel classification struggles to distinguish pro-B and pre–B I cells, namely the Fr. B and Fr. C subsets defined by Hardy.
The nomenclature for human B cell development has established gating strategies centered on BCR associated molecules: judgment relies on cyCD79a, CD19, cyIgμ, membrane IgM, and IgD, combined with cross validation using non BCR markers such as CD34, CD10, CD20, and CD38.
It is particularly worth noting that multiple studies have confirmed that B cell precursors (BCPs) do not undergo stage transitions synchronously as an entire population, but rather present as a continuum with asynchronous marker expression and overlapping states. In particular, pre–B I and pre-B II are further composed of multiple subdivided subsets.
The following table summarizes phenotypic markers and key events at each developmental stage of human and mouse B cells in developmental order:
Table 1. Phenotypes and molecular events at each stage of human B cell development
|
Stage |
Key Immunophenotype |
Ig/Rearrangement Status |
Other Molecular Events |
|
B lineage commitment |
cyCD79a⁺CD19⁻ (pro-B) |
/ |
PAX5 drives CD79a and CD19 expression and represses non-B-lineage genes |
|
pro-B |
CD34⁺CD10⁺, TdT⁺ |
IGH locus initiates rearrangement |
RAG1/2 expression; first wave of TdT |
|
pre-BI |
CD19⁺cyIgμ-IgM-, CD34⁺TdT⁺ (classical), CD34⁻TdT⁺ can also be detected |
D_H-J_H, V_H-D_H-J_H rearrangement |
CD10⁺, CD38⁺; CD20 is gradually upregulated but is independent of rearrangement status |
|
large pre-B (pre-BII L) |
CD19⁺cyIgμ⁺IgM⁻, proliferation |
V_H-D_H-J_H rearrangement, IgL light chain |
pre-BCR = Igμ + λ14.1/VpreB |
|
small pre-B (pre-BII S) |
CD19⁺cyIgμ⁺IgM⁻, resting |
V_L-J_L rearrangement, receptor editing window |
TdT second wave; CD40 expression |
|
immature B |
CD19⁺IgM⁺IgD⁻ |
Complete IgM-BCR |
Negative selection, anergy diversion; CBL loss leads to dysregulation at this stage |
|
transitional T1 |
CD38+++CD24+++CD10+IgD+CD27⁻ |
IgM⁺ |
High sensitivity to apoptosis, peripheral tolerance checkpoint |
|
transitional T2 |
CD38++CD24++CD10⁺IgD⁺CD27⁻ |
IgM⁺IgD⁺ |
CD23, IgD upregulation |
|
Mature naive |
CD38int CD24int CD10⁻IgD⁺CD27⁻ |
IgM⁺IgD⁺ |
ABCB1 activity positive |
|
GC B cells (dark zone) |
CXCR4hi CD83loCD86lo (CD86 downregulation) |
somatic hypermutation and class switching |
AID high expression; approximately 30% in S/G2M |
|
GC B cells (light zone) |
CXCR4lo CD83hiCD86hi; CXCR5, high surface Ig |
Affinity maturation /selection |
approximately 10%-15% in S/G2M |
|
Memory B |
No single marker; combined gating analysis with multiple markers is required. Mainly divided into classical CD27⁺ subsets (unswitched memory: CD27⁺IgD⁺; class-switched memory: CD27⁺IgD⁻IgG⁺/IgA⁺) and nonclassical CD27⁻IgD⁻ memory B cells. Overall profile: CD19⁺CD10⁻CD38⁻/lo; ABCs (Age-associated B cells) are CD11c⁺T-bet⁺ |
Mutation, mostly class switching |
Human-mouse correspondence requires experimental screening for confirmation. |
|
Plasma blast/Plasma cell |
CD138⁺CD38hi CD27hi CD20⁻ |
High frequency mutation (memory-derived) |
Antibody secretion; for human and mouse subset markers, surface and intracellular indicators need to be combined for comparison |
Table 2. Phenotypes and molecular events at each stage of mouse B cell development (Basel and Philadelphia nomenclature comparison)
|
Stage |
Hardy Fraction |
Immunophenotype |
Ig Rearrangement and Other Molecular Events |
|
Pre-Pro-B |
Fr. A |
B220low CD43+CD24low BP-1- |
Upregulation of EBF1 and PAX5 initiates B lineage specific genes; Rag1/2 begins expression; IgH/IgL in germline configuration |
|
Pro-B (early pro-B) |
Fr. B |
B220low CD43+HSAmid BP-1- |
D_H→J_H rearrangement; IL-7 signaling supports survival and proliferation |
|
Pre-BI (late pro-B) |
Fr. C |
B220lowCD43+HSAmid/hiBP-1+ |
D_H–J_H has rearranged, V_H→DJ_H rearrangement is ongoing; cells are proliferating |
|
Large pre-B (pre-BII_L) |
Fr. C' |
B220lowCD43+HSAmid/hiBP-1+ |
IgH+, IgL, V_H D_H J_H has rearranged; pre-BCR (μ chain + γ5/VpreB) drives proliferative expansion |
|
Small pre-B (pre-BII_S) |
Fr. D |
B220lowCD43-IgM- |
V_H D_H J_H has rearranged; V_L–J_L rearrangement is ongoing; cells exit the cell cycle and become quiescent |
|
Immature B (central tolerance) |
Fr. E |
B220lowCD43-IgM+IgD- |
BCR assembly is completed; autoreactive cells are eliminated through apoptosis, anergy, or receptor editing |
|
Mature B (enters circulation) |
Fr. F |
B220hi CD43- IgM+IgD+ |
Leaves the bone marrow and recirculates between splenic and lymph node follicles; cells are quiescent |
|
Transitional T1 |
/ |
CD93+1gMhiCD23lowIgDlow |
Major checkpoint for negative selection in the spleen, strong BCR crosslinking induces apoptosis, T1/T2 constitute the MZ; cells are quiescent |
|
Transitional T2 |
/ |
CD93+1gMhiCD23hiIgDlow |
CD23 and IgD are upregulated, continuing to receive BCR signal selection, the CD1d high subset serves as a prerequisite for MZ, and its development depends on Notch2; cells are quiescent |
|
Transitional T3 |
/ |
CD93+IgMlowCD23hiB220hiIgMlowIgDhi |
Identity undefined: a pre mature follicular stage, or cells that are deleted or anergic after encountering self-antigens. The fate is mature follicular B; cells are quiescent |
|
GC B cells (DZ subset) |
/ |
B220+GL7+CD95(Fas)+CXCR4hiCD83low |
Dark zone highly expresses AID and undergoes somatic hypermutation |
|
GC B cells (LZ subset) |
/ |
B220+GL7+CD95(Fas)+CXCR4lowCD83hi / CD86hi |
Light zone undergoes selection by FDC and Tfh; Bcl 6 is a key transcription factor for GC |
|
Memory B |
/ |
Double-negative subset (DN, CD80-PD-L2-); Double-positive subset (DP, CD80+PD-L2+); Single-positive subset (SP, CD80-PD-L2+ or CD80+PD-L2-) |
CD80 and PD L2 divide memory subsets with different functions; this classification is independent of antibody isotype (mouse memory B cells are not determined by CD27) |
|
Plasma blast/Plasma cell |
/ |
CD138(Syndecan-1) hiB220low |
Long lived plasma cells in the bone marrow continuously secrete antibodies, maintaining serum antibody levels |
Note: The Hardy fractions are a Basel staging nomenclature for mouse B cell development in the bone marrow proposed by Hardy and colleagues, named in alphabetical order (A–F), and do not include developmental stages in peripheral immune organs such as the spleen and lymph nodes. Under the Basel nomenclature, mouse pre-pro-B cells are B220+CD19-c-Kit+CD43+CD25-TdT+，pro-B/pre-BI为B220+CD19+c-Kit+CD43+CD25-TdT+ (the two are indistinguishable in this system), large pre-B cells are c-Kit-CD43-CD25+TdT-, small pre-B cells are CD25+CD40+TdT- , immature B cells are CD25+/−CD40+TdT-IgM+, and mature B cells are CD25-CD40+TdT-IgMlow IgD+. Mouse pre-B cells can also be enriched as CD2+sIgM-CD19+CD43-CD93+ cytoplasmic μ+, among which fewer than 10% of cells are cytoplasmic λ5+ and fewer than 5% of cells are c kit+.
03 Systematic comparison of marker differences between humans and mice
B cell development differs markedly between humans and mice, specifically at multiple levels including cell surface markers, intracellular transcription factor regulation, microenvironmental dependence, and kinetics. At the level of intracellular mechanisms, TdT and RAG define developmental stages through their expression windows: in humans, TdT shows two waves, corresponding to the order of IGH/IGL rearrangement, whereas in mice it is used to distinguish Fr. B/C from D/E. EBF1 and PAX5 are upregulated early during B lineage commitment and maintain the GFRA2⁺ state, thereby driving lineage exclusion. In addition, gene functional essentiality cannot be inferred solely from sequence conservation: for example, CBL is critical for human B cell development but redundant for T cells, whereas in mice CBL/CBL B are similarly redundant for BCR signaling. Transcriptome comparisons also show that most differential genes are specific to only one species, suggesting that genes are invoked in different functional contexts. Regarding the microenvironment, IL-7 deficiency in mice completely blocks the transition from pro-B to pre-B, and this effect is nonredundant; however, human IL-7Rα deficiency manifests as T⁻B⁺NK⁺, indicating that early B lymphopoiesis is not absolutely dependent on intact IL-7 signaling. Meanwhile, Flt3L, SCF/c-Kit, and CXCL12 cooperate with IL-7 to maintain bone marrow niche localization and survival, while Notch signaling participates in lineage diversion to the splenic marginal zone (MZ). At the levels of kinetics and anatomy, although both species complete the relocation of the generative site during the fetal liver to bone marrow transition, the degree of polarization of the AID compartment in germinal centers (5.2-fold in humans vs 1.5-fold in mice) and the magnitude of CD86 downregulation differ. Human MZ B cells can recirculate into the blood, whereas mouse MZ B cells are fixed in the spleen, which directly affects the identification of MZ like populations in peripheral blood. With increasing age, the B lymphopoiesis programs of both humans and mice change, and humans additionally develop age associated B cell subsets such as S100A8/A9⁺ and C1q⁺ cells.
The main differences in cell surface markers at each stage of B cell development between humans and mice are compared in the table below:
Table 3. Summary comparison of marker differences at each developmental stage of human and mouse B cells
|
Biological meaning |
Mouse markers |
Human markers |
Key differences |
|
Pan B cells/precursors |
B220 (CD45R) |
Combination of CD19, CD20, CD45RA, etc. |
Humans lack a single marker equivalent to B220; in mice, B220 is the core of B lineage gating but is not B lineage exclusive |
|
Early precursors |
CD93/AA4.1 (pre-B and immature stages) |
CD34 (pro-B/pre-BI) |
The two are not equivalent: humans use CD34 to mark precursors that "have not lost stem cell markers," whereas mice use CD93 to mark the precursor pool |
|
Precursor/maturation transition |
CD43, BP-1, CD25, S7 (CD2 fragment) |
CD10, CD38, CD20 |
Mice stratify by CD43± and BP-1; humans stratify by CD10/CD38 expression intensity, and in humans CD34/TdT can be uncoupled from rearrangement status |
|
Rearrangement enzymes |
TdT (Dntt), RAG1/2 |
TdT, RAG1/2 (two waves) |
Biologically consistent; human TdT shows two waves of expression, corresponding to IgH and IgL rearrangement |
|
Surrogate light chain |
λ5 (Igll1), VpreB |
λ14.1, VpreB |
Functionally equivalent; the human pre-BCR is composed of Igμ+λ14.1/VpreB |
|
Transitional/mature |
CD23, IgD upregulation; T1/T2/T3 stratified by CD21/35, CD23, IgM/IgD (mouse) |
T1/T2/T3 stratified by CD38/CD24/CD10 and ABCB1 activity |
Different stratification logic: mice rely on CD21/35 and CD23, humans rely on CD38/CD24 intensity and drug efflux activity |
|
Memory/activated |
No CD27 memory marker; relies on combinations of IgG1, CD38, CD80, etc. |
Combinations of CD27, CD21, CD11c, CD45RB, etc. |
Human and mouse memory B cell markers need to be established through unbiased screening, and cannot be directly transplanted |
|
Germinal center compartments |
CXCR4hi CD83lo (DZ), CXCR4lo CD83hi (LZ) |
Same as left (CXCR4/CD83 usable) |
Human CXCR4hi cells show weaker CD86 downregulation than in mice, so humans should not use CD86 as a substitute for CD83 |
|
Marginal zone |
CD21/35hi CD23- (splenic, non-recirculating, V region unmutated) |
CD27⁺IgMhi (V region mutated, can recirculate in peripheral blood) |
Human and mouse MZ differ in mutation status, recirculation behavior, and developmental dependence |
|
Innate like B-1 |
B-1a CD5⁺, B-1b CD5⁻; B220lo IgMhi CD11b⁺ CD23⁻ CD43⁺ |
CD20⁺ (or IgM⁺) CD27⁺CD38low/int CD43⁺CD70⁻ |
Human B-1 exhibits spontaneous IgG secretion and somatic hypermutation, differing from mouse B-1; phenotype and population identity remain controversial |
|
Plasma cells |
CD138（Sdc1）+B220lo/int |
CD138⁺CD38hiCD27hiCD20⁻ |
Humans use CD27/CD38 intensity and CD20 loss to aid determination, whereas mice use B220 downregulation as an aid |
In summary, given the differences in markers during human and mouse B cell development, the following pitfalls should be avoided when designing flow cytometry experiments:
(1) Avoid directly transplanting mouse gating schemes to humans: B220, CD43, and BP-1 have no equivalent system in humans, and human gating must be rebuilt using cyCD79a/CD19/cyIgμ/IgM/IgD/CD34/CD10/CD20/CD38.
(2) Avoid treating "population averages" as "stage boundaries": BCP marker expression is asynchronous, and pre–B I/pre-B II contain numerous internal subsets, so grouping solely by surface markers will obscure transitional state cells.
(3) Avoid treating "presence of a population" as "presence of a functionally equivalent population": the functional definitions of human B-1, MZ like, and memory B cells require combined gating analysis using multiple markers rather than relying on surface phenotype alone. Memory B cells are mainly divided into classical CD27+ subsets (unswitched memory: CD27+IgD+; class switched memory: CD27+IgD-IgG+/IgA+) and nonclassical CD27+IgD- memory B cells, overall presenting as CD19+CD10-CD38-/lo, among which ABCs (Age associated B cells) are CD11c+T-bet+.
04 Current research hotspots and latest advances in B cell research
With the rapid development of immuno precision medicine, antibody drug development, and CAR-B cell therapy, the differences in B cell development between humans and mice have long ceased to be an obscure knowledge point in basic research and have become a core research hotspot in the field, profoundly influencing both basic science and clinical translation.
The current research hotspots and latest advances related to B cells are summarized in the table below.
Table 4. Research hotspots and latest advances in B cell research
|
Research hotspots |
Core findings and mechanisms |
Key technologies / experimental models |
Clinical/physiological significance and prospects |
|
Single-cell and spatial omics reconstruct the B lymphopoiesis landscape |
Immature B cells show the lowest transcriptional activity and RNA velocity; naive B cell proliferation is restricted by the microenvironment; myeloid cells dominate stage dependent communication (TNF-adhesion pathways); S100A8/A9+ and C1q+ age-associated B cell subsets were identified, confirming that human B cells can secrete S100A8/A9 (exhibiting a senescence associated secretory phenotype). |
Combined single-cell transcriptome and BCR sequencing (bone marrow, tonsil, peripheral blood). |
Single-cell and spatial omics reconstruct the B lymphopoiesis landscape |
|
Central tolerance checkpoints: from receptor editing to novel pathogenic genes |
In ITP, V-J distance can serve as an indicator of receptor editing intensity; human CBL is critical for B cell development and function but largely redundant for T cells (the opposite of mice). |
Molecular mechanism studies (ITP/CBL models), genotype phenotype association analysis. |
Central tolerance checkpoints: from receptor editing to novel pathogenic genes |
|
Fetal developmental waves and "alternative" B lymphopoiesis |
Fetal progenitors efficiently generate innate-like effector cells; classical and alternative lineages follow staggered waves; CLPs divide into ALP and BLP, and BLPs are further divided into subsets; Ly6D and RAG-1 are acquired independently and in a nonhierarchical manner. |
Flow cytometry (Ly6D, GFRA2, BST1, etc.), progenitor developmental tracking. |
Fetal developmental waves and "alternative" B lymphopoiesis |
|
The debate over human B-1 cells |
The human B-1 phenotype is CD19+CD20+CD27+CD38low/intCD43+CD70-, with a biased BCR repertoire and the function of spontaneous secretion of natural antibodies; their existence and correspondence to mouse B 1 cells are increasingly accepted, yet human and mouse differences (such as SHM and spontaneous IgG) remain. |
Phenotypic identification, functional analysis. |
The debate over human B-1 cells |
|
Atypical B cells and immune aging |
CD11c+T-bet+ ABC are highly conserved across vaccination, infection, and autoimmunity, yet their origin and function remain undefined; the major obstacle is the inconsistent markers used across different studies. Together with age-associated B cells, they constitute a direction of aging. |
Single-cell sequencing, multi-context comparison. |
Atypical B cells and immune aging |
|
GC dynamics and memory B cell heterogeneity |
Human and mouse LZ/DZ can be distinguished using CXCR4/CD83, and the difference between the two zones is smaller than that between naive and GC B cells; the signature genes of the two species are highly conserved (92-93%), but local differences exist (CD86 downregulation is weaker in humans, and AID polarization toward the DZ is more pronounced). |
Cross-species unbiased screening systems, gene expression analysis. |
GC dynamics and memory B cell heterogeneity |
|
B cell targeted therapy and "immune reset" |
CD19/BCMA CAR-T can achieve deep B-cell-depletion, with some patients maintaining remission after treatment discontinuation, and the B cell pool is reconstituted with a naive phenotype; in vivo generated CAR-T cells eliminate pathogenic B cells in mice. |
CAR-T clinical trials (SLE, etc.), evaluation using overlapping reporter control systems, mouse models. |
B cell targeted therapy and "immune reset" |
|
Tumor infiltrating B cells and tertiary lymphoid structures |
TIL-B cells (including plasma cells) have predictive and prognostic value; their mechanisms include antigen presentation, construction of an "immune-hot" microenvironment, and alleviation of self-tolerance restrictions. |
Spatial omics, tumor immune microenvironment analysis. |
Tumor infiltrating B cells and tertiary lymphoid structures |
|
Methods and models |
A catalog of 4516 lncRNAs across 11 stages of mouse B cell development was established (regulated by PAX5); humanized mice experience species-specific selective pressures; the distribution of nonproductive rearrangements can distinguish rearrangement mechanisms from selection effects. |
RNA-seq, humanized mice, in vitro induction of B lymphopoiesis, and computational analysis of BCR repertoires. |
Methods and models
|
Current B cell research stands at the intersection of "high resolution dissection" and "explosive clinical translation." Future breakthroughs will depend on cautious interpretation of cross species data, standardization and unification of markers, and translation of single cell level findings into actionable therapeutic strategies (such as targeting specific B cell subsets or reshaping GC responses).
This article systematically reviews the core marker differences across the full developmental spectrum of human and mouse B cells and summarizes frontier research directions in the B cell field. In subsequent installments, we will continue to provide essential practical content on B cell development research, including detailed analysis of the design and analysis of flow cytometry panels for human and mouse B cell studies, as well as complete protocols for in vitro B cell activation and culture. We hope this will provide reference and support for the study design, experimental execution, and manuscript writing of fellow researchers.
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