Neutrophils are not classical antigen-presenting cells, but they can acquire antigen-presenting capabilities under specific conditions. In their resting state, freshly isolated neutrophils show little to no expression of the surface molecules needed to activate T cells. However, during infection, inflammation, and in certain cancers, a subset of neutrophils upregulates these molecules and can directly stimulate CD4+ T cell responses, functioning in a way that resembles professional antigen-presenting cells like dendritic cells and macrophages.
What Makes a Cell an Antigen-Presenting Cell
To present antigens to T cells, a cell needs two things on its surface: MHC class II molecules (which display fragments of foreign proteins) and costimulatory molecules (which send the “go” signal that activates T cells). The classical professional antigen-presenting cells, dendritic cells, macrophages, and B cells, express both of these constitutively or readily upon encountering a threat. Freshly isolated blood neutrophils express neither MHC class II nor costimulatory molecules at meaningful levels, which is why they’ve historically been excluded from the antigen-presenting cell category.
How Neutrophils Gain Antigen-Presenting Ability
Several cytokines can flip the switch. GM-CSF appears to be the most potent trigger, though interferon-gamma and IL-3 can also induce MHC class II expression on neutrophils. In a 2024 proteomics study, researchers identified an antigen-presenting phenotype in human blood neutrophils during the early phase of bacterial bloodstream infections. GM-CSF activates this transformation through a specific signaling cascade that ultimately turns on the gene for CIITA, the master regulator of MHC class II expression.
Phagocytosis itself can also trigger the change. When neutrophils engulf antibody-coated red blood cells, they upregulate both MHC class II and costimulatory molecules (CD40 and CD80) within about 20 hours. Importantly, only the neutrophils that actively performed phagocytosis gained these markers. Bystander neutrophils in the same environment did not, suggesting the trigger is closely tied to the act of engulfing and processing material.
Not all costimulatory molecules come along for the ride equally. CD40 and CD80 are reliably upregulated on activated neutrophils, but CD86 and CD83 tend to remain low or absent even after phagocytosis. This incomplete costimulatory profile is one reason neutrophil antigen presentation is weaker than what dendritic cells achieve.
How They Compare to Dendritic Cells
Neutrophils can present antigens to memory CD4+ T cells both in laboratory settings and in living tissue, but they do so far less efficiently than professional antigen-presenting cells. In direct comparisons, dendritic cells induced the highest levels of T cell proliferation, monocytes were somewhat lower but still potent, and neutrophils showed a markedly lower but consistent ability. Even when neutrophils did upregulate the necessary surface molecules, expression levels remained substantially below those found on dendritic cells and monocytes.
The tradeoff is in numbers. Dendritic cells are rare but excel at T cell stimulation. Neutrophils are the most abundant white blood cell in circulation, making up 50 to 70 percent of all white blood cells. Even if each individual neutrophil is an inefficient presenter, their sheer volume means their collective contribution to immune responses could be meaningful, particularly at sites of heavy inflammation where neutrophils vastly outnumber dendritic cells.
Where Antigen-Presenting Neutrophils Are Found
Antigen-presenting neutrophils have been identified in peripheral blood, inflamed tissues, and lymph nodes. During inflammation, neutrophils are recruited not only to the site of infection but also to draining lymph nodes via both blood vessels and lymphatic vessels. Lymph nodes are where T cell activation primarily happens, making neutrophil presence there particularly relevant. Within lymph nodes, neutrophils interact with both innate and adaptive immune cells and can influence antigen presentation either directly (by presenting antigens themselves) or indirectly (by transferring antigens to dendritic cells).
Neutrophils also travel to lymph nodes under normal, non-inflammatory conditions, potentially playing a role in immune surveillance and shaping early adaptive immune responses before a full-blown infection takes hold.
Aged Neutrophils and Sepsis
A particularly well-characterized subset is the “antigen-presenting aged neutrophil,” or APAN. These are neutrophils that have been in circulation longer than usual and display a distinct surface profile combining aged-cell markers with antigen-presentation markers. In sepsis, APANs engage in direct antigen presentation to CD4+ T cells, driving T cell activation, proliferation, and differentiation into a pro-inflammatory subtype. This process generates high levels of IL-12, a signaling molecule that amplifies inflammation. In the context of sepsis, where runaway inflammation is already the core problem, this neutrophil-driven T cell activation can worsen organ damage rather than help.
Roles in Autoimmune Disease and Cancer
In autoimmune conditions like lupus and rheumatoid arthritis, altered neutrophil subsets appear more frequently. Low-density neutrophils, which are enriched in these patients, can promote vascular damage and oxidative stress. Dysregulated neutrophil cell death can also modify self-proteins and expose them to the adaptive immune system, potentially fueling the autoimmune cycle by presenting the body’s own molecules as threats.
In cancer, the picture is more nuanced. A large-scale analysis of neutrophil states across cancer types identified 10 distinct transcriptional profiles, with antigen presentation being one of three dominant states found across multiple cancers. These antigen-presenting neutrophils, marked by high HLA-DR expression, were among the most enriched neutrophil subsets in tumor environments. Critically, they could induce T cell responses against tumor-specific proteins (neoantigens), raising the possibility that neutrophils might be harnessed therapeutically. Because neutrophils can be loaded with a broad range of tumor antigens without the genetic engineering that T cell therapies require, they represent an intriguing and potentially more accessible avenue for immunotherapy.
The Bottom Line on Classification
Neutrophils are not professional antigen-presenting cells in the traditional sense. They don’t constitutively express MHC class II or a full set of costimulatory molecules the way dendritic cells do. But calling them incapable of antigen presentation is no longer accurate either. Under inflammatory conditions, specific cytokine signals, or after phagocytosis, a subset of neutrophils acquires the molecular machinery for antigen presentation and can activate CD4+ T cell responses at levels comparable to splenic antigen-presenting cells in some experimental settings. The emerging consensus treats neutrophil antigen presentation as conditional and context-dependent: a capability that is normally silent but becomes functionally relevant during infection, sepsis, autoimmune flares, and within tumor microenvironments.