In the previous tutorial we talked about how immune cell surface receptors work,
and the ways that a signal carried by a ligand can propagate inside the cell. But we did this
in a general way with regards to the receptors. Now it’s time to talk about the specific kinds of
receptors that immune cells can express. There are hundreds of different surface receptors,
such that we could devote a whole series to these proteins and not get through them all,
so for brevity let’s focus on five main categories of immune cell receptors.
The first category is antigen receptors. Antigen receptors allow immune cells to sense the presence
of infectious microbes as well as damaged or diseased self cells, and there are two main types:
pattern recognition receptors and antigen-specific lymphocyte receptors.
Pattern recognition receptors, or PRRs, include Toll-like receptors, or TLRs,
nucleotide-binding oligomerization domain-like receptors, also called NOD-like receptors,
or NLRs, C-type lectin receptors, or CLRs, and Rig-1-like receptors, or RLRs.
PRRs are able to recognize pathogen-associated molecular patterns, or PAMPs, and
damage-associated molecular patterns, or DAMPs. PAMPs are molecular signatures that are only found
on microbes, things like bacterial glycolipids, or single-stranded DNA from viruses, or the distinct
sugars found in fungal cell walls. PAMPs also tend to be molecules that microbes need in order
to survive. This prevents them from evolving away from recognition by the immune system.
DAMPs, on the other hand, are molecules made by self cells, but are often molecules that
should only be intracellular, like ATP or the DNA-binding protein HMGB1. If a cell surface DAMP
receptor is able to bind to these molecules, it’s because there are dead or damaged cells nearby.
Unlike pattern recognition receptors, which are germline encoded, and encompass a broad range of
antigens, antigen-specific lymphocyte receptors, as their name implies, are extremely specific.
Each individual B and T cell goes through a process of genetic rearrangement in their antigen
receptor genes to randomly generate receptors that could recognize any type of antigen.
Because of this genetic rearrangement, each B and T cell only expresses one type
of antigen-specific lymphocyte receptor, making each cell a “specialist” for a different antigen.
Now on to the second type. As we mentioned in the previous tutorial, immune cells often need
more than to simply bind and recognize microbial antigens. Many of them require costimulation from
other cells to confirm that there really is a threat, and to give the cells “permission” so
to speak, to become fully activated and carry out their various effector functions. As we will see
throughout this series, this sort of two-signal system, in which immune responses need to detect
two distinct signals to become activated, is present throughout the immune system.
Costimulation is carried out by costimulatory receptors. T cells express CD28, which is a
costimulatory receptor for protein ligands called CD80 and CD86, which are expressed on antigen
presenting cells like B cells, macrophages, and dendritic cells. Binding of CD80 or 86 causes T
cells to receive survival and proliferation signals after binding to their target antigen.
Another costimulatory receptor on T cells is ICOS, which stands for inducible costimulator.
This binds to ICOS-ligand on antigen presenting cells. ICOS binding is especially important
for preparing CD4 T cells to help B cells. T cells are not the only cells that
need to receive costimulation. CD40 on antigen-presenting cells can bind to CD40
ligand on T cells. This interaction is critical for optimizing antibody production in B cells,
but it also sends stimulatory signals to the T cells as well. CD40 binding on dendritic cells
increases their expression of other costimulatory ligands like CD80 or 86,
creating a positive feedback loop that sustains activation of both cell types.
Now on to the third type. Activated immune cells are capable of causing a lot of damage to both
pathogens and self tissues, so it’s important to be able to keep these responses well-regulated.
One way to keep activated immune cells in check is through inhibitory receptors. One example is
the receptor CTLA-4 on T cells, which stands for cytotoxic T-lymphocyte-associated protein 4. Like
CD28, CTLA-4 also binds to CD80 or 86 on antigen presenting cells, but it binds with a higher
affinity than CD28. CTLA-4 competes with CD28 for CD80 or 86 binding, meaning that less CD28 can
bind and stimulate activation, thus preventing activation when in low enough concentration.
Additionally, when CTLA-4 is bound, it actually sends inhibitory signals to the T cell.
PD-1 is another important inhibitory receptor expressed on activated immune cells, especially T
cells, that binds to PD-L1 or PD-L2, which are expressed on a variety of cell types, including
cancer cells. When PD-1 on activated T cells binds, it can promote T cell apoptosis. Inhibitory
receptors are also important for regulating natural killer cell activity. Natural killer cells
are not antigen specific, but become activated through a balance of activating receptors,
which can bind to PAMPs and DAMPs, and inhibitory receptors, which bind to surface proteins that are
common on healthy self cells. This prevents the natural killer cells from killing healthy cells.
Moving on to the fourth type. Costimulatory receptors allow cells to communicate that
are right next to each other, but how do cells communicate with other cells that are far away?
One way is through cytokines and cytokine receptors.
Cytokines are soluble protein signals that immune cells use to communicate with one another.
They can be released by immune cells or by cells in infected or damaged tissues. Cytokines can
help dictate which cell types dominate an immune response, depending on whether an infection is
bacterial, viral, or parasitic. Cytokines are also crucial for determining whether an immune response
leans more towards a pro-inflammatory state, or a more regulated, tissue repair state.
Many cytokines are critical for promoting immune cell growth, development, and proliferation.
And finally, for number five, we have chemokine receptors.
Chemokines are similar to cytokines in that they are soluble protein messengers,
but their role is to help guide immune cells to the site of infection or damage.
Most chemokine receptors are large G-protein coupled receptors. When a chemokine binds
its receptor, it causes changes in adhesion and motility that help the cell migrate to infected
tissues. Cytokines and chemokines are very important signaling molecules, so we will want to
discuss them in much greater detail than we have so far. So let’s move forward and do just that.