Unlike T and B cells, NK cells do not express a specific antigen receptor. They are nevertheless capable of recognising and eliminating abnormal cells (e.g., foreign, infected, stressed or subject to a process of malignant degeneration) while sparing healthy cells because they can effectively discriminate “self” from “non-self”.
Activation of NK cells involves inhibitory and activating receptors. It can be the result of activation signals, but also the consequence of a reduction in inhibition.
Actors involved
Mechanism
Where?
NK cells are sentinel cells found in the bloodstream and can be recruited to inflammatory sites by chemokines chimiokines. NK cells can activate against any abnormal cell present in the body, regardless of its location.
When?
Although NK cells are players in innate immunity (no somatic rearrangement of receptors, no antigenic specificity), they possess certain characteristics of adaptive immunity: they must undergo an education process before being able to be active, in particular through contact with Class I HLA molecules encountered in their environment.
This education “teaches” them to inhibit their cytotoxic activity in order to be tolerant towards normal cells, and to activate otherwise. At the same time, this step gives them all the potential necessary for an effector action (e.g., stock of mRNA coding for interferon-γ, perforin and granzyme B) without activating them.
How is this done?
NK cells are primarily known for their cytotoxic functions but they are also involved in the regulation of the immune response through the secretion of cytokines/chemokines.
1. Cytotoxicity of NK cells
- Direct cytotoxicity
The NK cell expresses both “activating” and “ inhibiting” receptors of its cytotoxic activity. It permanently integrates these activating and inhibitory signals and activates according to its overall activation/inhibition balance.
If a cell in the body expresses abnormally (quantitatively or qualitatively) the ligands to its receptors, the NK cell is likely to become activated, either by reducing its inhibition and/or increasing its activation.
- ADCC-mediated cytotoxicity
NK cells have receptors that recognize constant fragments (Fc) of immunoglobulins (FcR, or CD16). This allows them to recognize opsonised cells - in particular by IgG - and to lyse them.
- Cytotoxicity mechanisms
Two cytotoxicity mechanisms are used by NK cells:
- Exocytosis of lytic granules
For example, perforin (membrane permeabilisation molecule) and granzymes (proteases), which lead to cell lysis after destruction of the membrane.
- Expression of cell death receptor ligands
NK cells constitutively express cell death ligands (e.g., CD95L and TRAIL) whose receptors are expressed by the target cell.
2. Production of cytokines and chemokines
NK cells are capable of rapidly producing cytokines. In an inflammatory context, they will secrete, in particular:
- Interferon-γ which promotes phagocytosis by macrophages, the maturation of dendritic cells, as well as the adaptive immune response by promoting the polarization of CD4+ T cells towards the Th1 pathway.
- TNF-α which has multiple pro-inflammatory actions, both local (e.g., stimulation of phagocytosis, promotion of diapedesis, etc.) and systemic (e.g., stimulation of inflammatory proteins secreted in the liver, hypothalamic effect with the onset of fever, etc.).
- Growth factorswhich promote the synthesis and recruitment of immune actors (e.g., GM-CSF, Granulocyte Macrophage-Colony Stimulating Factor or G-CSF, Granulocyte-Colony Stimulating Factor, which stimulate haematopoiesis).
- Many other chemokines allowing the recruitment and activation of macrophages, dendritic cells, neutrophils, etc.
Outside of an inflammatory context, NK cells are also capable of secreting immunosuppressive cytokines.
Consequences
In organ transplantation, NK cells will activate according to three major mechanisms.
1. Underexpression of Class I HLA molecules
Stressed cells may underexpress their Class I HLA molecules in an attempt to escape the cytotoxicity of CD8+ T cells.
The body’s cells are subject to permanent stress, physiological (e.g., cell division, exercise of their function, etc.) or not (e.g., environmental exposures, infections, etc.). One of the functions of the immune system, and in particular CD8+ T cells, is to eliminate these cells infected or damaged by stress. To eliminate these cells, CD8+ T cells recognise peptides embedded in Class I HLA molecules. CD8+ T cells have in fact been educated to tolerate self-peptides, and eliminate cells presenting peptides other than those of the self (see T cell ontogeny).
One of the escape mechanisms for an abnormal cell therefore consists of reducing the expression of Class I HLA molecules to “ escape” CD8+ T cells. In doing so, they expose themselves to the activation of NK cells!
In this case, the inhibitory receptors of Class I HLA molecules (classical and non-classical) no longer have a ligand, which induces a drop in the inhibitory signal.
The peptides embedded in the HLA-E molecule correspond to part of the Class I HLA molecules. If a cell no longer expresses or expresses fewer HLA-A, -B or -C molecules, HLA-E will no longer be or will be less expressed on the surface of this cell.
2. Induction of MICA expression
MICA is a non-classical Class I HLA molecule, encoded by a gene located near HLA-B. MICA expression is zero in the basal state, but can be induced by cellular stress, particularly after organ transplantation.
Increased expression of MICA by the cell
Increased engagement of NKG2D activating receptor
Increase in activating signal
Activation of the NK cell
3. Cell expressing different HLA molecules
The genes encoding classical Class I and II HLA molecules are the most polymorphic in the human species. It is therefore very unlikely that two unrelated individuals will have the same HLA typing.
The NK cell will be activated both via direct and indirect cytotoxicity mechanisms.
- Direct cytotoxicity
The recipient’s NK cells have been educated to maintain the activation/inhibition balance in the presence of the recipient’s HLA molecules. When an organ with a different HLA typing is transplanted, this balance is disrupted. The donor’s cells can therefore become the target of the recipient’s NK cells, particularly when the donor does not have the ligands necessary for inhibition. It is the theory of “ missing self”. - Indirect cytotoxicity (ADCC)
The recipient can synthesise antibodies recognising the HLA molecules of the donor cells, which allows the NK cell to lyse the opsonized cell.
What needs to be remembered
NK cells are lymphocytes whose properties place them at the border between innate and adaptive immunity. In fact, they do not have a specific immunoreceptor (no TCR or BCR) but they must however undergo an education process to be fully active. This education occurs through the interaction between KIR receptors carried by NK cells and Class I HLA molecules present on all nucleated cells and platelets. This process makes the NK cell capable of activating in particular against cells with Class I HLA molecules different from “self”, which is common in the context of transplantation.
The activation state of the NK cell depends on the overall balance of signals received by its inhibitory receptors on the one hand, and activating receptors on the other. Once activated, the NK cell exerts cytotoxic functions in the same way as the activated CD8+ T cell and via the same mediators (exocytosis of lytic granules and induction of cell death).