Atypical B cells are a broad research category of human B cells that often show low or absent CD21 and CD27. Some studies also identify CD11c, the transcription factor T-bet, or increased inhibitory receptors. The label does not describe one universally defined cell type, a diagnosis, or a single functional state. Different marker panels can capture different populations, so the disease, subset, assay, and result must be named whenever their behavior is discussed.
Atypical B-cell populations have been described in chronic infections such as malaria and HIV and in systemic autoimmune disease, including systemic lupus erythematosus (SLE). Some populations respond less readily to B-cell-receptor stimulation, while others show distinct activation, antibody-repertoire, or transcriptional features. “Atypical” therefore describes a phenotype observed in a particular experiment, not proof that every cell in the category is exhausted, harmful, or beneficial.
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What the term atypical B cell means
B cells are lymphocytes that can develop into antibody-secreting plasma cells, form memory populations, and present antigen to other immune cells. In human studies, investigators traditionally distinguish major B-cell populations with surface markers such as CD21 and CD27. Cells called atypical B cells (AtB, ABCs, or atypical memory B cells) often fall outside the usual marker pattern for classical memory B cells.
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The central point is that atypical B cell is an umbrella term. It groups cells with recurring phenotypic features, but it does not establish a single lineage, maturation route, tissue location, or job. A 2025 overview by Iñaki Sanz stresses that the populations are functionally diverse and should be studied by direct functional experiments rather than by relying on historical labels (Sanz, “Human Atypical B Cells. An Overview,” Immunological Reviews, 2025).
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“Atypical” also does not mean that the cells are inherently abnormal in a clinical sense. It means that their measured phenotype differs from the conventional comparison population used in that study. A cell can be atypical relative to classical memory B cells without being diseased, useless, or permanently dysfunctional.
Which markers are used to identify them?
There is no universal flow-cytometry gate for atypical B cells. Investigators choose combinations of markers according to the disease, tissue, species, and question being tested. The most frequently reported pattern in human work is reduced or absent CD21 together with absent or reduced CD27. Additional markers can strengthen a study-specific definition but do not, by themselves, identify every atypical population.
| Marker or feature | How it is used in studies | Important limitation |
|---|---|---|
| CD21 | Low or negative CD21 is common in reported atypical populations. | CD21 loss is not unique to one lineage or disease; its meaning depends on the rest of the panel. |
| CD27 | Many atypical populations are CD27-negative, unlike the conventional CD27-positive memory comparison. | CD27 status alone cannot define an atypical B cell. |
| CD11c | Used in some studies to describe an activated or atypical phenotype. | CD11c alone is not a universal identifier. |
| T-bet | This transcription factor is detected in some studied atypical subsets. | Its presence varies by context and does not make all T-bet-positive cells equivalent. |
| Inhibitory receptors | Increased expression is reported in some chronic-infection populations. | Expression can reflect a particular disease state or activation history rather than a defining requirement. |
| B-cell-receptor responsiveness | Functional assays sometimes test how strongly cells respond to B-cell-receptor stimulation. | A reduced response in one population or assay does not establish universal exhaustion. |
These features should be read as a panel and a context, not as a checklist that applies identically everywhere. The 2017 review of chronic infectious diseases emphasizes that overlapping names and marker combinations can identify nonidentical cells (“Atypical memory B cells in human chronic infectious diseases: An interim report,” Current Opinion in Immunology, 2017).
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1Clear out junk files and repair common Windows errors2Scan for outdated or missing drivers - takes under a minute3Repair Windows errors before they cause bigger problemsHow atypical populations differ from classical memory B cells
Classical memory B cells are a broad conventional reference population, not a perfectly uniform cell type either. In many human studies, CD21 and CD27 help identify this reference compartment. Atypical populations commonly have less CD21 and CD27, and some have CD11c, T-bet, or inhibitory receptors. Functional differences are reported, but they vary with the disease and the exact subset examined.
| Feature | Classical memory B cells (general comparison) | Atypical B-cell populations (common reported tendency) |
|---|---|---|
| Surface phenotype | CD21 and CD27 commonly contribute to the conventional memory definition. | Often CD21-low or negative and CD27-negative; CD11c may be included in some panels. |
| Transcriptional profile | Used as a conventional memory reference in many experiments. | Some subsets express T-bet and show transcriptional programs associated with particular inflammatory environments. |
| Inhibitory receptors | Not the defining feature in the general contrast. | Increased expression is reported in some chronic-infection subsets. |
| B-cell-receptor response | Provides the reference response in assays of memory-cell activation. | Some chronic-infection populations respond less readily to B-cell-receptor stimulation. |
| Interpretation | A conventional, still variable memory category. | An umbrella category whose origin and function depend on the study context. |
This is a qualitative comparison, not a universal diagnostic or laboratory gate. Two laboratories can use different combinations of CD21, CD27, CD11c, T-bet, and other markers and both use the term “atypical” for the resulting cells.
Why one label covers several cell populations
Chronic antigen exposure, inflammatory cytokines, tissue conditions, and a person’s prior immune history can all influence B-cell phenotype. As a result, cells grouped together by low CD21 and CD27 may differ in developmental history, receptor repertoire, activation state, and ability to make antibody. Marker overlap can therefore indicate shared pressures without proving that the cells are one stable lineage.
The terminology reflects this history. Articles may use atypical B cells, atypical memory B cells, atMBCs, or ABCs. Infection literature has also used “exhausted” or “tissue-like” memory B cells. These expressions overlap in some settings but are not perfectly interchangeable. A careful article or laboratory report should state which markers and functional criteria were actually used.
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Malaria
Malaria is one of the settings in which expanded atypical populations have been studied most extensively. A 2021 single-cell analysis reported related transcriptional profiles among atypical B-cell clusters from malaria, HIV, and autoimmune disease, while also finding important heterogeneity within the category. In malaria, the study reported that interferon-gamma (IFN-γ) drove expansion of atypical populations in the experimental system. That is evidence for a mechanism in the malaria context, not a rule for every atypical B cell (Holla et al., “Shared transcriptional profiles of atypical B cells suggest common drivers of expansion and function in malaria, HIV, and autoimmunity,” Science Advances, 2021).
The same work described malaria-associated subsets with differing antibody-receptor repertoires and activation characteristics. Consequently, even within malaria, “atypical B cells” does not identify one behaviorally uniform population.
HIV and other chronic infections
Chronic infection can be accompanied by atypical memory B-cell populations with altered surface markers and, in some studies, increased inhibitory-receptor expression. Some chronic-infection populations show weaker responses when their B-cell receptor is stimulated in vitro. That result may reflect the particular infection, subset, stimulation protocol, or tissue source; it should not be converted into a universal claim that all atypical cells are exhausted.
Systemic lupus erythematosus and autoimmunity
Atypical phenotypes are also reported in systemic lupus erythematosus and other systemic autoimmune settings. Expansion or association with disease does not demonstrate that the cells cause autoimmunity. They may be responding to inflammatory signals, participating in antigen presentation or antibody responses, or representing several populations with different effects. Reviews of chronic infection and systemic autoimmunity describe the field as unresolved, with disease-specific features and consequences still being worked out (“Atypical B cells in chronic infectious diseases and systemic autoimmunity: puzzles with many missing pieces,” Immunity, 2022).
What do atypical B cells do?
No single function applies to the entire category. Depending on the population and assay, investigators have reported differences in B-cell-receptor signaling, activation markers, transcriptional programs, antibody repertoires, and responses to inflammatory cues. A measured reduction in one response is not equivalent to complete cellular inactivity.
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Reduced receptor responsiveness in some subsets
Some chronic-infection populations respond less readily to B-cell-receptor stimulation than the comparison memory cells. This finding is often described as a feature of functional exhaustion or dysfunction, but the historical label can overstate what the experiment shows. A receptor-stimulation assay tests one pathway under defined conditions; it does not measure every possible activity a cell might perform in tissue.
Heterogeneous activation and antibody repertoires
The 2021 single-cell study found malaria-associated atypical subsets with differing activation characteristics and antibody-receptor repertoires. Such variation argues against treating all CD21-low, CD27-negative cells as interchangeable. One subset might be poised for a different antibody response from another, even if both fall under the same broad phenotypic label.
Inflammatory signals can shape expansion
In the malaria experiments reported by Holla and colleagues, IFN-γ promoted expansion. Cytokine-driven expansion demonstrates that the local immune environment can influence the size of an atypical population; it does not by itself prove whether the resulting cells protect against infection, contribute to pathology, or do both under different conditions.
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A useful report answers four questions before assigning meaning:
- Which cells were measured? State the tissue, species, disease status, and gating markers, including whether CD21, CD27, CD11c, T-bet, or inhibitory receptors were required.
- What was the comparison? Identify the classical memory, naive, or other reference population used in the experiment.
- What assay was performed? Separate surface-phenotype measurements from B-cell-receptor stimulation, antibody secretion, transcriptional profiling, or repertoire analysis.
- What did the experiment actually show? Describe an association, expansion, reduced response, or cytokine effect without inferring causation that was not tested.
This approach prevents three common errors: treating a marker as a universal definition, calling every atypical population exhausted, and assuming that expansion in a disease proves pathogenicity. The 2025 Sanz review summarizes the principle this way: “Finally, we proposed that given the degree of functional diversity of these cells, specific functional studies rather than historical descriptions should be used to understand their actual role under different conditions.”
Are atypical B cells harmful or protective?
The answer depends on the population and the disease. A study showing expansion during malaria, HIV, or SLE establishes a relationship with that condition; it does not by itself show that the cells initiated or worsened disease. Likewise, a reduced response in a stimulation assay does not prove that the cells cannot make useful antibodies or perform other immune functions.
To claim a harmful or protective role, investigators need direct functional evidence tied to a defined subset: for example, a measured effect on pathogen control, autoantibody production, antigen presentation, or disease-relevant tissue behavior. Until such evidence is available, the precise wording is that an atypical population is associated with, expanded in, or responsive to a particular condition.
What the label means for patients and readers
Finding the phrase “atypical B cells” in a paper or laboratory report does not automatically mean a person has a separate disease, an immune deficiency, or irreversible B-cell damage. The term is mainly a research classification. Its significance depends on the measured markers, the clinical setting, and whether a validated test connects that population to a treatment decision.
Readers should be cautious with claims that quote one percentage of atypical B cells without naming the disease, population, marker definition, assay, and original study. No general prevalence figure applies across malaria, HIV, SLE, and healthy comparison groups because the gates and populations differ.
Bottom line
Atypical B cells are best understood as a family of study-defined B-cell phenotypes, commonly marked by low CD21 and CD27 and sometimes by CD11c, T-bet, or inhibitory receptors. They differ from classical memory B cells in phenotype and, in selected settings, in receptor responsiveness or transcriptional behavior. Their diversity is the essential qualification: the same umbrella label can cover cells with different origins and functions. Interpret every result by naming the disease, subset, markers, assay, and observed outcome rather than assuming that “atypical” means exhausted, pathogenic, or protective.
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