Beyond their role as frontline soldiers, a remarkable subset of neutrophils secretly directs the immune system's decisions, holding the power to either protect or harm our bodies.
Imagine your immune system as a sophisticated army. For decades, neutrophils were seen as the infantry—frontline troops that swarm invaders, releasing antimicrobial chemicals and sacrificing themselves in a blaze of glory. Recent scientific discoveries, however, have revealed a more intriguing reality: some neutrophils are actually undercover diplomats, capable of suppressing immune responses and negotiating peace treaties in the midst of inflammatory battles.
Frontline soldiers specialized in phagocytosis and pathogen elimination
Undercover diplomats capable of suppressing immune responses
This newly discovered population, known as suppressive neutrophils, plays a critical role in everything from fighting cancer to managing sepsis. Their dysfunction can mean the difference between health and disease, making them one of the most exciting frontiers in immunology today.
For over a century, neutrophils were classified as simple foot soldiers of the innate immune system—specialized in phagocytosis, degranulation, and the production of reactive oxygen species to eliminate pathogens 8 . Their short lifespan of approximately 7-24 hours in circulation further reinforced this perception as disposable frontline defenders 7 .
Neutrophils seen as simple foot soldiers with short lifespan and basic functions
Researchers noticed unexpected immunosuppressive behaviors in cancer and chronic inflammation
Identification of three distinct neutrophil subsets, including CD16bright/CD62Ldim suppressive neutrophils 3
Suppressive neutrophils recognized as sophisticated immune regulators with therapeutic potential
The paradigm began to shift when researchers noticed that in certain conditions like cancer and chronic inflammation, neutrophils exhibited unexpected behaviors. Instead of promoting inflammation, they seemed to suppress immune activity, particularly against T cells—the orchestrators of adaptive immunity 6 .
In 2012, a landmark study identified three distinct subsets of circulating human neutrophils during acute systemic inflammation. Among these, the CD16bright/CD62Ldim subset demonstrated a remarkable ability to inhibit T-cell proliferation, marking the first clear characterization of suppressive neutrophils in humans 3 .
The similarity between these cells and granulocytic myeloid-derived suppressor cells (G-MDSCs)—immature myeloid cells known to suppress immune responses in cancer—became increasingly apparent, suggesting neutrophils could adopt immunosuppressive phenotypes under specific conditions 6 .
Neutrophils are far from a uniform population. Through advanced techniques like single-cell RNA sequencing, scientists have identified multiple neutrophil states with specialized functions:
Undergo changes in marker expression and function over time 7
Neutrophils that have infiltrated tumor microenvironments, further categorized into antitumor N1 and protumor N2 phenotypes based on their polarization 8
| Marker | Traditional Neutrophils | Suppressive Neutrophils | Function |
|---|---|---|---|
| CD16 | Bright | Bright | Fc receptor, antibody-mediated phagocytosis |
| CD62L | Bright | Dim | Lymph node homing, adhesion |
| CD11b | Bright | Bright | Inflammation, cell adhesion |
| CD11c | Variable | Bright | Integrin, cell adhesion |
| CD66b | Positive | Highly Positive | Cell activation, adhesion |
| PD-L1 | Low | High | Immune checkpoint, T-cell suppression |
The CD16bright/CD62Ldim signature has become a hallmark for identifying suppressive neutrophils in human blood 3 . This unique combination allows these cells to be distinguished from their pro-inflammatory counterparts through flow cytometry analysis.
Suppressive neutrophils play contradictory roles depending on the context—sometimes beneficial, sometimes harmful.
Suppressive neutrophils can become formidable allies to tumors. Research on lung cancer neutrophils revealed that while they maintain some antitumor cytotoxicity through neutrophil extracellular traps (NETs), they lose their ability to inhibit cancer cell migration—potentially facilitating metastasis 2 . These neutrophils show increased expression of PD-L1, an immune checkpoint protein that dampens T-cell responses, effectively disarming the body's anticancer defenses 2 .
A 2025 study found that low-density neutrophils in sepsis patients expressed high levels of PD-L1 and demonstrated impaired phagocytosis and apoptosis 1 . Most importantly, these neutrophils actively suppressed T-cell proliferation—primarily through PD-L1 expression rather than reactive oxygen species—providing a mechanism for the immunosuppressive phase that follows initial sepsis hyperinflammation 1 .
Suppressive neutrophils also serve vital protective functions. By restraining overzealous immune responses, they prevent excessive tissue damage and autoimmune reactions. Recent research has identified neutrophil-derived vesicles (LAND-Vs) that help control complement activation and facilitate inflammation resolution 5 . This discovery highlights how neutrophils, even during aging or after death, can prolong their functionality to regulate immune responses and minimize collateral damage 5 .
The same suppressive mechanisms that can harm in cancer and sepsis can protect against autoimmune diseases and excessive inflammation.
To understand how researchers study suppressive neutrophils, let's examine a key experiment from a landmark 2025 study published in Scientific Reports 1 :
Blood samples from ICU patients with sepsis (n=24), non-sepsis ICU patients (n=10), and healthy controls (n=20)
Double-layered density gradient centrifugation to isolate low-density neutrophils (LDN) and normal-density neutrophils (NDN)
Analysis with fluorescent antibodies against specific surface markers using FACS Canto II cytometer
| Parameter | Sepsis NDN | Sepsis LDN | Significance |
|---|---|---|---|
| Surface Markers | Lower CD66b, CD63, CD11b | Higher CD66b, CD63, CD11b, CD184, PD-L1 | Distinct phenotype identifies suppressive subset |
| CD62L Expression | Higher | Lower | Altered adhesion and migration capabilities |
| Phagocytosis | Normal | Impaired | Reduced pathogen clearance capacity |
| Apoptosis | Normal | Delayed | Extended lifespan in circulation |
| T-cell Proliferation | Minimal suppression | Significant suppression | Direct inhibition of adaptive immunity |
Perhaps the most clinically significant finding was that LDN levels could predict secondary infections and mortality in sepsis patients with remarkable accuracy—area under the curve values of 0.79 and 0.84, respectively 1 . This suggests suppressive neutrophils could serve as valuable biomarkers for identifying patients at risk of sepsis-induced immunosuppression.
The experimental data further demonstrated that T-cell suppression was primarily mediated through PD-L1 rather than reactive oxygen species, as adding anti-PD-L1 neutralizing antibody restored T-cell proliferation, while a ROS scavenger (N-acetyl cysteine) did not 1 .
Studying suppressive neutrophils requires specialized reagents and techniques. Here are key tools researchers use to isolate and characterize these cells:
| Reagent/Technique | Function | Application Example |
|---|---|---|
| Density Gradient Centrifugation | Separates blood components based on density | Isolation of LDN from PBMC fraction 1 |
| Flow Cytometry Antibodies | Identify specific surface proteins | Detecting CD16bright/CD62Ldim suppressive neutrophils 3 |
| Anti-PD-L1 Neutralizing Antibody | Blocks PD-L1/PD-1 interaction | Testing mechanisms of T-cell suppression 1 |
| Annexin V/Propidium Iodide | Detects apoptotic cells | Measuring neutrophil survival and death 1 |
| T-cell Proliferation Assay | Measures T-cell growth and activity | Quantifying immunosuppressive effects 4 |
| Reactive Oxygen Species Scavengers | Neutralizes reactive oxygen species | Determining ROS role in suppression mechanisms 1 |
The growing understanding of suppressive neutrophils has opened exciting therapeutic possibilities:
Targeting neutrophil-mediated immunosuppression represents a promising approach. Potential strategies include inhibiting neutrophil recruitment to tumors, blocking their suppressive mechanisms (such as PD-L1), or reprogramming protumor N2 neutrophils to antitumor N1 phenotypes 8 .
Detecting suppressive neutrophils could help identify patients entering the immunosuppressive phase of sepsis, allowing targeted immunostimulatory therapies. The 2025 study demonstrated that a simple microscopic-based method using Wright's staining in PBMC could detect these cells, potentially enabling less expensive monitoring in clinical settings 1 .
Enhancing the suppressive functions of neutrophils might help control excessive inflammation in conditions like rheumatoid arthritis or autoimmune disorders, though this approach requires careful balancing to avoid increased infection risk.
As research continues, scientists are working to develop more precise methods for manipulating these cells—potentially harnessing their power to fine-tune immune responses across a spectrum of diseases.
The discovery of suppressive neutrophils has transformed our understanding of one of the most abundant cell types in our immune system. No longer viewed as simple foot soldiers, these sophisticated regulators demonstrate remarkable plasticity, capable of either amplifying or restraining immune responses depending on the context.
As research advances, the potential to target these cells for therapeutic benefit continues to grow. From improving cancer immunotherapy outcomes to managing the complex phases of sepsis, suppressive neutrophils represent both a challenge and an opportunity—a reminder that in immunology, as in life, even the most familiar characters can surprise us with hidden depths.