For the past few tutorials, we’ve been talking about how immune cells communicate with one
another.
And where we left off last, we were discussing cytokine receptors and chemokine receptors.
Now let’s talk about cytokines and chemokines themselves, as well as some common naming
strategies for these small, soluble proteins.
Recall that cytokines are used by immune cells use to communicate with one another, while
chemokines guide the migration and localization of immune cells.
Non-immune cells can also release cytokines and chemokines to alert and recruit immune
cells.
Before we jump into the functions of these important signaling molecules, let’s start
with some basic cytokine nomenclature.
Cytokines are grouped into structurally similar families, and are named with a prefix or suffix
indicating which family they are from, along with another identifier, like a number or
a Greek character.
Some major families of cytokines include the interferons, abbreviated as IFN-, tumor necrosis
factor, or TNF-, and colony stimulating factors, which have -CSF as a suffix.
One of the largest families of cytokines is the interleukins, whose name refers to communication
between leukocytes, or white blood cells.
We now know that many non-immune cells also release cytokines, so while the term “interleukin”
isn’t entirely accurate, it is still widely used.
Because cytokine and chemokine names are often grouped by structural similarity and organized
in order of discovery, we are going to introduce them based on similar function.
Learning about cytokines and chemokines can feel a bit like being force-fed alphabet soup,
but knowing how to interpret their names and having a basic idea of what many of them do
will be quite helpful.
Now, when we talk about an immune response, there are actually several common types or
varieties that are defined by distinct cytokine and cellular profiles, and these types are
tailored to fight different kinds of pathogens.
Each of these varieties of immune responses are named for the type of helper T cell that
orchestrates the response.
We’ll talk much more about these helper cells later in the series, but right now,
let’s just focus on the groups of cytokines that tend to function together, as well as
the major outcomes of these signaling profiles.
The first group of cytokines we will discuss are Th1 cytokines.
These are the ones that drive a Type 1, or Th1 immune response, named as such because
it is driven by Type 1 T helper cells.
The Th1 response is known for promoting cellular immunity against intracellular pathogens like
viruses and some bacteria, meaning that this response is geared towards activating CD8
T cells and natural killer cells, which can both detect and kill virally infected cells,
destroying the virus in the process, as well as macrophages, which are great at killing
pathogens they’ve ingested.
For simplicity’s sake, we won’t discuss all the cellular sources of these cytokines,
just some of their broad targets and effects.
Here’s the lineup of some of the cytokines involved in a Th1 response:
IL-2 is best known for being absolutely critical for T cell survival, proliferation, and differentiation.
IL-12 activates natural killer cells, which kill virally infected cells, and helps polarize
helper T cells to be even more Type 1-like.
TNF-α can cause cell death and has broad-reaching pro-inflammatory effects on many cell types.
Lymphotoxin-α or LT-α is closely related to TNF-α, and it can signal in its soluble
form, as a homotrimer, or in its membrane-bound form, where it complexes with lymphotoxin-β
or LT-β.
Both LT-α and LT-β can kill chronically infected cells, activate macrophages, and
are important for lymphoid tissue development.
IFN-γ is a type II interferon.
It has direct antiviral activity on cells, and helps make virally infected cells more
likely to be detected by killer T cells.
IFN-γ also activates macrophages, and blocks polarization of type 2 helper T cells, which
we’ll talk about next.
After Th1 cytokines, we will discuss Th2 cytokines.
This group belongs to the Th2 response, which is controlled by type 2 helper T cells.
Th2 responses activate humoral responses, meaning that the immune response is dominated
by the action of antibodies, which are produced by activated B cells, instead of killer T
cells.
It also is characterized by a strong presence of eosinophils, basophils, and mast cells.
Th2 responses are characteristic of a response to parasitic worms called helminths, and can
also promote wound healing and tissue repair.
Th2 responses are also responsible for most of the negative effects that occur with allergies
and asthma.
Here are some of the most important Th2 cytokines.
IL-4 is critical for polarizing helper T cells to a Type 2 phenotype.
It promotes mast cell growth and development in the bone marrow, stimulates eosinophils,
and activates B cells.
IL-5 drives eosinophil development in the bone marrow.
IL-13 signals B cells to make a class of antibody called IgE, which is one of the hallmarks
of a Th2 response.
IL-25 helps amplify Th2 responses by inducing IL-4, IL-5, and IL-13, and activates type
2 innate lymphoid cells.
IL-10 enhances B cell activation and antibody production, while suppressing expression of
Th1 cytokines.
For the third group we will jump up to Th17 cytokines.
These belong to the Th17 response, named as such because it is driven by helper T cells
that secrete high levels of IL-17.
Th17 responses are especially good at controlling fungi and extracellular bacteria, because
of their ability to recruit a strong neutrophil response.
An overly active Th17 response can lead to negative health consequences like irritable
bowel syndrome.
Here the relevant structures are as follows.
IL-17 stimulates production of the chemokine IL-8, also known as CXCL8, which is a strong
neutrophil chemoattractant.
IL-22 acts on epithelial cells in the gut, skin, and lung – which are barrier cells
that are right at the front lines of many bacterial and fungal infections – to promote
cell proliferation and tissue healing, as well as production of antimicrobial peptides.
And IL-23 helps polarize helper T cells to a Th17 phenotype.
The fourth and final category of T cell associated cytokine responses we will talk about is from
regulatory T cells, or Tregs.
There is actually one more major subset of CD4 T cells and these are the follicular T
helper cells.
These are the cells that help activate B cells in lymphoid tissue, but we’ll talk about
those in another tutorial.
Back to Tregs, these work to dampen an immune response in order to prevent excessive tissue
damage and the risk of developing autoimmunity.
IL-10 is an important regulatory cytokine we’ve already discussed.
Another one is TGF-β. TGF-β has a huge range of functions, including promoting tissue repair
and wound healing, but it is also anti-inflammatory.
It achieves this activity by promoting Treg development, inhibiting B cell proliferation,
and inhibiting activated macrophages.
So with cytokines covered, now let’s switch gears and talk about chemokines.
Chemokines help regulate all aspects of cell movement and migration, including promoting
changes in cell adhesion and motility, causing cytoskeleton rearrangement, and guiding cell
movement towards a certain stimulus in a process called chemotaxis.
Chemokines don’t stop there, though.
Remember how well-organized lymph nodes are?
A huge part of that meticulous organization comes from chemokine signaling activity shepherding
immune cells to their proper locations within lymphoid tissue.
Before we get started, chemokine nomenclature can also get a little confusing, so let’s
break it down.
There are 2 major families of chemokines.
Those are the CC family and the CXC family.
CC chemokines are named as such because there are 2 adjacent cysteine amino acid residues
near the amino terminus of the protein.
Each of these residues is represented with the letter C. CXC chemokines also have 2 cysteine
residues near the amino terminus, but they are separated by a single, variable amino
acid, marked by the letter X. Here’s a tip: If you find CC or CXC followed by an L (for
example, CCL2), the L stands for ligand.
CCL2 is therefore a chemokine.
If CC or CXC is followed by an R, the R stands for receptor, and you know that this protein
is a receptor for either a CC or a CXC chemokine.
Let’s look at some CC chemokines.
These tend to induce migration of lymphocytes and monocytes.
CCL2 or MCP-1 promotes Th2 immunity and release of histamine by basophils.
CCL3 or MIP-1α recruits monocytes, macrophages, and neutrophils, and promotes Th1 immunity.
CCL4 or MIP-1β recruits monocytes and natural killer cells.
CCL5 or RANTES recruits eosinophils, T cells, and basophils to infection sites, and can
also activate natural killer cells.
Then there are CXC chemokines.
These tend to promote neutrophil migration, and they include the following.
CXCL8, also known as IL-8, recruits neutrophils to infected tissues.
CXCL7 is released from activated platelets.
This chemokine activates neutrophils and promotes angiogenesis, which is the growth of new blood
vessels.
This is especially important following injury and during tissue repair.
CXCL1, CXCL2, and CXCL3 are similar to CXCL7.
They promote angiogenesis, activate neutrophils, and stimulate fibroblast proliferation.
The difference is that these chemokines are released by endothelial cells, fibroblasts,
and monocytes, instead of platelets.
As we mentioned before, chemokines are also very important for directing lymphocytes to
where they need to go in the lymph node and other lymphoid tissues.
CCL21 is secreted by stromal cells in the lymphoid tissue to recruit dendritic cells.
CCL18 and CCL19 are then secreted by dendritic cells, which recruit T and B cells to the
lymph node.
And CXCL13 is secreted by follicular dendritic cells to recruit B cells to the B cell zone
by binding CXCR5.
As you can see, there are a lot of different cytokines and chemokines, and by signaling
together, they can allow for highly nuanced immune responses, depending on the nature
of the threat.
This survey may have seemed rather tedious, but it was important to get these details
out of the way so that we can really dig into the specifics of immune response.
So let’s move forward and take a look at innate immunity.