2025.07.18
Within the human immune system, B cells serve as core members of adaptive immunity, constructing a long-term defense against pathogens through antibody production and immune memory formation. Their development proceeds in a strictly ordered manner, while the diversity of functional subsets endows immune responses with exceptional flexibility and specificity. This article will delve into the developmental stages of B cells, key regulatory mechanisms, and the classification and characteristics of functional subsets.
B cell development originates from hematopoietic stem cells (HSCs) in the bone marrow, undergoing a series of gene rearrangements and phenotypic changes to ultimately differentiate into mature B cells. This process can be divided into the following critical stages (Figure 1):
1. Pro-B cells: At this stage, V(D)J recombination of immunoglobulin heavy chain (IgH) genes occurs, forming functional heavy chains. Studies indicate that pro-B cells retain minimal HSC characteristics when participating in mitochondrial autophagy pathways (e.g., the Pink1/Park2 pathway), suggesting they have entered lineage commitment[1].
2. Pre-B cells: Cells that successfully express IgH proliferate and form pre-B cell receptors (pre-BCRs), with light chain genes initiating rearrangement. Single-cell sequencing reveals that pre-B cells specifically express 203 circular RNAs (circRNAs), potentially involved in regulating the cell cycle[2].
3. Immature B cells: After completing light chain rearrangement, cells express intact BCRs (IgM) on their surface but must undergo negative selection to eliminate self-reactive clones. At this stage, 219 circRNAs are significantly enriched in the cell transcriptome[2].
4. Mature B cells: These migrate to the spleen or lymph nodes and further differentiate into follicular B cells (FO B cells) or marginal zone B cells (MZ B cells). Mature B cells specifically express 207 circRNAs, which may participate in maintaining their homeostatic functions[2].
Notably, B cell development is intricately regulated by transcription factor networks. For example, Bcl6 influences the differentiation of memory B cell subsets (e.g., CD62L+ memory B cells) by regulating genes such as Bcl2 and Zeb2; its overexpression impairs the development of CD62L+ memory B cells[3][3].
Mature B cells are not a homogeneous population but are divided into multiple subsets based on phenotype, localization, and function, each with distinct roles (Table 1):
1. Naïve B cells
o Characteristics: Unstimulated by antigens, they express IgM and IgD on their surface.
o Function: Serving as the "reserve force" of immune responses, they activate and enter germinal centers upon antigen stimulation.
2. Memory B cells
o Heterogeneity: Memory B cells include multiple functionally distinct subsets, such as CD62L+ and CD44+ subsets, which exhibit significant differences in transcriptional profiles and reactivation capacities[3]. The CD62L+ subset has stronger homing abilities, while the CD44+ subset may participate in rapid antibody responses.
o Regulatory mechanisms: Overexpression of Zeb2 specifically inhibits the development of CD62L+ memory B cells, suggesting a molecular switch for subset differentiation[3].
3. Plasma cells
o Function: Terminally differentiated "antibody factories" that secrete large quantities of immunoglobulins. In autoimmune diseases (e.g., systemic lupus erythematosus, SLE), abnormal plasma cell activity produces autoantibodies that drive disease progression[4][5].
4. Non-Canonical B Cell Subsets
o Age-associated B cells (ABCs): These highly express CD11c and T-bet, expanding in chronic infections (e.g., SARS-CoV-2) and autoimmune diseases. Studies show that ABC expansion is closely linked to interferon-λ (IFN-λ) signaling[6].
o B1 cells: With self-renewal capacity, they secrete natural antibodies (e.g., anti-phosphocholine antibodies) and anti-inflammatory factor IL-10, participating in mucosal immunity and homeostasis maintenance[7].
Abnormalities in B cell subsets are associated with various diseases:
1. Autoimmune Diseases: In SLE, CD11c+CD21- B cells (also termed "double-negative B cells") expand, with elevated expression of BAFF receptors (e.g., mBAFF and BCMA) on their surface, promoting autoantibody production[8]. Additionally, excessive plasma cell activation directly correlates with anti-dsDNA antibody levels[9].
2. Tumor Immunity: Tumor-infiltrating B cells (TIL-Bs), including naïve B cells and germinal center B cells, influence the tumor microenvironment through antigen presentation or antibody secretion. For example, increased infiltration of CD20+ B cells in tumor tissues may correlate with prognosis[10].
3. Immunodeficiency: Developmental arrest of B cells leads to antibody deficiency syndromes, while defects in memory B cell subsets impair vaccine responses[11][12].
In recent years, single-cell sequencing has revealed finer heterogeneity among B cell subsets. For instance, pseudotime trajectory analysis has clarified the differentiation path from pro-B cells to plasma cells[13]. Additionally, spatial transcriptomics has identified that monocytoid cells may share similar gene expression profiles with "atypical memory B cells"[14].
In the future, therapies targeting B cell subsets (e.g., BAFF inhibitors, CD20 monoclonal antibodies) or modifying B cell functions via gene editing[15] will provide new strategies for treating autoimmune diseases, infections, and tumors.
Conclusion
B cell development and subset differentiation exemplify the precise regulation of the immune system. Understanding their molecular mechanisms and functional diversity not only provides keys to studying disease mechanisms but also paves new paths for precision immunotherapy.
References
1. Elucidating the mitochondrial function of murine lymphocyte subsets and the heterogeneity of the mitophagy pathway inherited from hematopoietic stem cells.
2. Whole-Transcriptome Profiling and circRNA-miRNA-mRNA Regulatory Networks in B-Cell Development.
3. CD62L expression marks a functionally distinct subset of memory B cells.
4. The Multiple Roles of B Cells in the Pathogenesis of Sjögren's Syndrome.
5. Transcriptomic analysis of B cells suggests that CD70 and LY9 may be novel features in patients with systemic lupus erythematosus.
6. B Cell Activation and Plasma Cell Differentiation Are Promoted by IFN-λ in Systemic Lupus Erythematosus.
7. Splenic B1 B Cells Acquire a Proliferative and Anti-Inflammatory Profile During Pregnancy in Mice.
8. BAFF system expression in double negative 2 activated naïve and activated memory B cells in systemic lupus erythematosus.
9. Activation of circulating TFH17 cells associated with activated naive and double negative 2 B cell expansion and disease activity in systemic lupus erythematosus patients.
10. Action of circulating and infiltrating B cells in the immune microenvironment of colorectal cancer by single-cell sequencing analysis.
11. Defining a normal reference range for B cells A key to diagnosing humoral inborn errors of immunity.
12. B-Cell Immunophenotyping to Predict Vaccination Outcome in the Immunocompromised - A Systematic Review.
13. A Single-Cell Transcriptome Profiling of Anterior Kidney Leukocytes From Nile Tilapia ().
14. Nodal reactive proliferation of monocytoid B-cells may represent atypical memory B-cells.
15. Challenges and opportunities in gene editing of B cells.
