Natural killer (NK) cells are a type of white blood cell that play a critical role in the innate immune system. They help defend the body against infections and cancer by killing compromised cells. However, NK cells are also increasingly being recognized as important regulators of inflammation and autoimmunity. This has raised questions about whether NK cells can directly trigger inflammatory responses.
What are natural killer cells?
NK cells are lymphocytes – a type of white blood cell – that circulate in the blood and lymph system. They account for around 10% of all lymphocytes. NK cells are considered part of the innate immune system because they can respond quickly to threats without prior sensitization. This contrasts with B cells and T cells, which require activation and clonal expansion before defending against specific antigens.
NK cells got their name from their ability to kill compromised host cells without prior activation. They play a key role in the rejection of tumors and cells infected by viruses. NK cells can directly induce apoptosis (programmed cell death) in target cells. They also secrete cytokines like interferon-gamma to recruit and activate other immune cells.
How do natural killer cells recognize threats?
NK cells must be able to discriminate between healthy host cells and compromised or foreign cells. They rely on a sophisticated set of activating and inhibitory receptors on their cell surface:
- Activating receptors recognize stress ligands and non-self markers that are upregulated on abnormal cells. This triggers NK cell activation.
- Inhibitory receptors recognize MHC class I molecules, which are expressed by most healthy cells. Engagement of these receptors prevents NK cell activation against healthy cells.
This system allows NK cells to selectively target diseased cells while sparing healthy cells. However, if MHC class I expression is downregulated – as can occur in some cancers or infections – NK cells lose inhibition and become hyperactivated.
How do NK cells kill target cells?
Once activated, NK cells can directly kill compromised cells through several mechanisms:
- Release of cytotoxic granules – NK cells contain specialized lysosomes called cytotoxic granules. These contain perforin and granzymes. Upon release, perforin forms pores in the target cell membrane while granzymes enter and trigger apoptosis.
- Death receptor signaling – NK cells express death ligands like FasL and TRAIL that can engage death receptors on target cells and induce apoptosis.
- Antibody-dependent cell cytotoxicity – NK cells express Fc receptors that bind the Fc region of antibodies. This allows NK cells to kill antibody-coated cells through cytotoxic granule release.
In addition to direct cytotoxicity, activated NK cells secrete cytokines like IFN-gamma and TNF-alpha. These stimulate other immune cells and help shape the developing immune response.
What is the role of NK cells in inflammation?
In addition to their cytotoxic functions, NK cells can produce various inflammatory cytokines and chemokines, such as:
- TNF-alpha
- IFN-gamma
- GM-CSF
- CCL3, CCL4, CCL5
- CXCL8
Through cytokine and chemokine secretion, NK cells can recruit and activate other innate immune cells like neutrophils, monocytes, and dendritic cells. This amplifies inflammatory responses. NK cells can also interact with adaptive immune cells like T cells and B cells to shape immune responses.
In some conditions like autoimmunity and chronic infection, dysregulated NK cell responses can contribute to excessive or prolonged inflammation. However, NK cells also have regulatory capacities that can help resolve inflammation. For example, they can kill overactive immune cells and produce anti-inflammatory cytokines like IL-10.
Do natural killer cells directly trigger inflammation?
Considering their inflammatory capacities, an important question is whether NK cells can directly initiate an inflammatory response in the absence of other immune cells. There are a few key considerations:
- Most evidence indicates that NK cells on their own have limited capacity to directly provoke inflammation. While they can secrete some inflammatory cytokines, the amounts are small compared to other innate immune cells.
- NK cell activation and inflammatory cytokine production is enhanced by synergistic signals from other cell types, particularly dendritic cells and T helper cells.
- NK cell depletion or deficiency alone is not sufficient to prevent inflammatory disease in animal models. Depletion of other immune cells like T cells and neutrophils is required.
- Isolated human NK cells do not secrete significant inflammatory cytokines unless stimulated with immune complexes or cytokines like IL-12, IL-15, and IL-18.
Based on this evidence, current thinking is that NK cells require additional signals from other immune cells to drive substantial inflammatory responses. On their own, they likely play a limited initiating role.
Can natural killer cells amplify ongoing inflammation?
While they may have a limited capacity to directly provoke inflammation on their own, considerable evidence indicates that NK cells can amplify inflammatory responses that are already underway:
- Once inflammation is initiated by other immune cells like dendritic cells, NK cells can be recruited to inflamed tissues in large numbers.
- Pro-inflammatory cytokines like IL-12, IL-15, IL-18, and type I IFNs produced during immune responses can directly activate NK cells.
- Interaction of NK cells with activated dendritic cells and T helper cells further stimulates NK cell activation and inflammatory cytokine production.
- NK cells recruited to inflamed tissues can kill local cells indiscriminately via cytotoxic granules, fueling more inflammation.
So while NK cells may not be key direct initiators of inflammation, they can serve to amplify and prolong ongoing inflammatory responses through recruitment, activation, and effector functions.
What are some examples of NK cell-driven inflammation?
There are several examples where NK cells likely contribute to inflammatory disease pathogenesis:
- Rheumatoid arthritis – Expanded NK cells are found in the joints and correlate with disease severity. NK cells likely interact with other immune cells to drive chronic joint inflammation.
- Psoriasis – NK cells infiltrate psoriatic skin lesions. They may interact with dendritic cells and T cells to provoke inflammation.
- Asthma – Allergen exposure recruits activated NK cells to the airways where they secrete cytokines that amplify allergic inflammation.
- Colitis – Pro-inflammatory cytokines draw NK cells to the inflamed colon where they contribute to tissue damage.
- Atherosclerosis – Activated NK cells are found in atherosclerotic plaques. Their cytokines may promote plaque inflammation and instability.
In most of these conditions, NK cells are likely not the initiators of inflammation. But once inflammation is triggered by other means, NK cells are drawn in and act to amplify the inflammatory cascade.
Can natural killer cells suppress inflammation?
While NK cells can promote inflammation in some contexts, they also have the capacity to limit or resolve inflammatory responses through several regulatory mechanisms:
- NK cells can kill activated immune cells like dendritic cells, neutrophils, and T cells to dampen responses.
- They can produce anti-inflammatory cytokines like IL-10 that counteract inflammation.
- Interaction of NK cells with regulatory T cells can enhance immune suppressive responses.
- During viral infections, NK cells can lyse virus-infected cells and reduce pro-inflammatory triggers.
So in certain inflammatory contexts, NK cells have the ability to play a regulatory role. Their influence likely depends on the cytokine milieu, presence of other immune cells, and nature of the inflammatory stimulus.
Conclusion
In summary, while NK cells have considerable inflammatory capacity, current evidence suggests they likely play a limited direct role in initiating inflammation on their own. Their ability to drive inflammation appears to require synergy with other innate and adaptive immune cells responding to an initial trigger. However, once inflammation is already underway, NK cells can clearly amplify inflammatory cascade through recruitment, activation, and effector functions. Their influence seems to depend on context – they can both promote and resolve inflammation. More research is needed to fully elucidate the factors governing pro- versus anti-inflammatory NK cell responses.