Cell-mediated immunity of natural killer and CD8 cells

Definitions & Key takeaways

https://osmosis.org/learn/Cell-mediatedimmunityofnaturalkillerandCD8_cells

Natural killer cells are innate lymphocytes that play a critical role in the early response to viral infection and cancer. They detect virus-infected cells and eliminate them before they can spread the infection. CD8 cells are cytotoxic T lymphocytes that recognize and kill infected or mutated cells. CD8 cells also secrete cytokines that stimulate the immune response. Both natural killer cells and CD8 cells are essential in protecting against cancer and infections.

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The key cells of the adaptive immune response are the lymphocytes - the B and T cells. And there are two types of T cells.
Helper T cells which express CD4 on their surface, and cytotoxic T cells which express CD8 on their surface. Helper T cells primarily support other immune cells, whereas cytotoxic T cells kill cells that are infected with a pathogen or are cancerous.
Cytotoxic T cells, along with natural killer cells, are part of cell mediated immunity. Cell mediated immunity refers to the part of the immune response that’s based on cellular interactions, and cannot be transferred through serum from one person to another.
That makes sense since both natural killer and cytotoxic T cells need to interact directly with a target cell in order to destroy it.
Now, when a T cell is initially formed it’s considered naive. Later when that T cell encounters an antigen in the lymph node- it gets activated or primed - and turns into an effector T cell.
This process of priming requires two signals. The first signal is the antigen itself, which is usually presented on an MHC molecule on the surface of an antigen presenting cell like a macrophage or dendritic cell.
Cytotoxic T cells respond to intracellular antigens - like viruses, intracellular bacteria, and tumor antigens. The naive cytotoxic T cell needs a high level of stimulation to become activated and it relies on a process called cross-presentation to reach that level.
In cross-presentation macrophages or dendritic cells take up the antigen and then present it to the cytotoxic T cell. These antigens typically come from extracellular pathogens or from tumor cells or virally infected cells.
The first signal is that the antigen has to bind perfectly to the T cell receptor or TCR. The second signal is called costimulation - and it’s when a ligand called CD28 on the surface of a T cell binds to a ligand called B7 on the antigen presenting cell.
This region, which includes the T cell receptor which binds to the MHC-Antigen, and CD8 and CD28 which bind with B7, is called the immune synapse.
Once the T cell receives both of these signals, a number of changes occur within the cell that transforms the naive T cell into a cytotoxic T cell.
The activated T helper cell also begins making lots of cytokine IL-2, and upregulates its IL-2 alpha receptor. The IL-2 receptor has three protein components - alpha, beta, and gamma.
A naive T cell only expresses the beta and gamma components of the IL-2 receptor, but these have low affinity for IL-2, in contrast to the alpha component of the IL-2 receptor which has a high affinity for IL-2.
Using just the beta and gamma components is like trying to eat an apple with only your lips and tongue. And upregulating the alpha component is like using your teeth to take a big bite out of the juicy apple - much more effective and satisfying!
As a result active T cells make more IL-2 and then bind to the IL-2 that they make with their IL-2 receptors - a form of autocrine stimulation - a cell stimulating itself.
In response to the IL-2, the activated T cell starts to rapidly undergo cell division - a process called clonal expansion.
The cytotoxic T cell is now a lean, mean, killing machine that’s ready to attack. This activated cytotoxic T cell only needs to see its antigen in the context of MHC I in order to kill the cell.
In other words, it no longer needs that costimulatory signal from CD28. And the way that cytotoxic T cells find potential targets is by going cell-to-cell binding non-specifically.
They use adhesion molecules like LFA-1 on their surface to bind to molecules like ICAM which is found on the surface of most cells.
After loosely binding in this way, it tries to bind to that cell’s MHC I molecule. If the cytotoxic T cell cannot bind because the correct antigen isn’t present, then the cytotoxic T cell disengages and moves on to the next cell.
On the other hand, if the cytotoxic T cell does bind strongly to the antigen, then the two cells engage with each other more strongly.
The LFA-1 molecule changes its confirmation to bind ICAM more tightly - a sort of death embrace. The cytotoxic T cell has been waiting for this moment - it rearranges its cytoskeleton and a region forms on its surface called the supramolecular activation cluster or SMAC.
The SMAC has a central zone called the central supramolecular activation cluster or cSMAC and an outer zone called the peripheral supramolecular activation cluster or pSMAC.
The SMAC twins. cSMAC is where you can find the proteins needed for antigen recognition mainly CD8 and the CD3 complex which includes the T cell receptor.
The T cell receptor is of course bound to the MHC I molecule on the target cell. The pSMAC is where the LFA-1 is found.
So, the two cells are locked in this tight death embrace when the cytotoxic T cell starts to release it’s granules which contain perforin and granzymes.
Perforin starts to punch holes in the lipid bilayer of the target cell, and granzymes, which are serine proteases, activate caspases in the target cell making it undergo apoptosis.
Fortunately the killing is swift and specific, meaning that neighboring cells don’t get harmed. And the cytotoxic T cell usually disengages from its target cell and moves on to another potential target cell before the first cell has even completed apoptosis.
Like cytotoxic T cells, natural killer cells also identify target cells and deliver granzymes and perforin. The difference is that they’re part of the innate immune response and therefore don’t need to identify a specific antigen on a target cell to kill it.
Instead, natural killer cells follow a series of kill or don’t kill instructions to decide on a target cell. First- natural killer cells have activation receptors - like NKG2d - which recognize cell surface molecules that are often found on the surface of cells infected with viruses, intracellular bacteria, or cancerous cells.
Natural killer cells also have inhibitory receptors - like Killer Immunoglobulin-like Receptor or KIR and NKG2a - which recognize the molecules like the MHC class I molecule and instruct the natural killer cell not to kill the target cell.
To be clear, this is not an antigen specific response - so it doesn’t matter what antigen is present in the MHC I molecule when NKG2a binds it.
Instead, what matters is that the MHC I molecule is present, and that it’s a person’s own MHC I molecule - rather than some foreign MHC I molecule.
So, if the MHC I molecule is absent or if it’s foreign, like in organ transplantation, then the natural killer cell will kill the target cell.
This works because many viruses try to hide from our immune responses by making their host cell decrease expression of MHC class I molecule, which would normally present viral antigens, leaving them susceptible to killing by cytotoxic T cells.
So if there’s a cell that doesn’t have MHC class I molecules, then a natural killer cell will kill it. Typically a signal from an inhibition receptor overrides an activation receptor - a cell is innocent until proven guilty.
So if KIR recognizes MHC I on the surface and NKG2d recognizes a viral antigen, then the target cell might not be killed.
But this also depends on the number of receptors bound and how tightly they’re bound, so if there are more activating receptors bound than inhibitory receptors, and if the strength of binding is higher for the activating receptors relative to the inhibitory receptors, then the target cell will be killed.
Natural killer cells are also able to kill using a method known as antibody dependent cell mediated cytotoxicity or ADCC.
That’s where an infected cell with viral proteins gets bound by IgG antibodies specific for those antigens. The natural killer cell has a cell surface molecule called CD16 that’s able to bind on the constant - or Fc portion - of the antibody.
This sends a very strong activating signal to the natural killer cell, allowing it to destroy the target cell. In addition to destroying target cells, natural killer cells also produce cytokines like interferon-gamma to activate macrophages.
Alright, as a quick recap, cytotoxic T cells and natural killer cells are both capable of killing target cells by releasing cytotoxic granules that contain perforin and granzyme directly at their intended cell.
Cytotoxic T cells do this in an antigen specific manner, looking for their specific antigen expressed on the MHC I molecule of the target cell.
Natural killer cells are non-specific and kill a target cell based on the number or strength of activating versus inhibiting signals they receive.
Natural killer cells are also capable of killing cells using antibody dependent cell mediated cytotoxicity with the help of IgG.