We now have a general sense of the types of immune cells that exist,
as well as their functions. But the much trickier thing to understand
is precisely how these functions are elicited on the molecular level,
and a substantial portion of this series will be devoted to elucidating these complex mechanisms.
Right now we are going to talk about how immune cells communicate with one another, as well as how
they sense and respond to changes. This happens primarily through receptor-ligand interactions.
So what are receptors and ligands? We answered this question in some
detail in the biochemistry series, where we learned that receptors are special proteins
which receive chemical signals, in the form of small molecules that act as ligands, meaning that
they interact with the active site of the receptor and elicit a conformational change in the receptor
that triggers the propagation of that signal. To review the basics regarding receptor structure
and function, check out that tutorial now. But if we are up to speed on what receptors
are and what they do, let’s learn about them in the context of immune activity.
With immune cells, receptors are specifically found in the cell membrane.
This means that immune cell receptors must have two domains. First, an extracellular domain
that recognizes particles in the extracellular space, and second, an intracellular domain
that translates recognition by a receptor into biochemical action within the cell.
Most receptors are single transmembrane proteins whose domains span the intra- and extra-cellular
spaces. However, some receptors are protein complexes, with separate proteins teaming
up to play the roles of extracellular sensing and intracellular signaling.
So the question is, how does a receptor sense changes in the extracellular environment? Once
again, this is achieved by binding to molecules called ligands. Each receptor is specific to a
particular ligand, and once this ligand binds to its receptor, it initiates a downstream
signaling cascade. Depending on the receptor, a ligand can be a sugar, a lipid, another protein or
peptide, or even a nucleic acid. A ligand can be free-floating in the blood or interstitial fluid,
like soluble antigen, or it can be attached to the surface of another cell, meaning that the
ligand-expressing cell needs to be physically close enough to the receptor-expressing cell
for the ligand to bind and initiate signaling. The important thing here is that generally,
receptor/ligand pairings are extremely specific. This specificity allows the cell
to have increased sensitivity in responding to changes in the molecular environment, and allows
it to be able to distinguish relatively subtle differences between similar types of molecules.
By expressing a diverse repertoire of receptors, a cell is armed with the ability to “see”,
so to speak, many different molecules that carry important information for immune cells.
Next, after a receptor binds to its extracellular ligand, how does it translate that binding event
into meaningful intracellular activity? This happens through a process called
signal transduction. The first step of signal transduction is to convert the extracellular
binding event into intracellular biochemical cues. One way to do this is to equip the intracellular
side of a receptor with enzymatic activity. When the ligand binds, the conformational change that
binding induces activates the enzyme, and kicks off a chain reaction of signaling within the cell.
Many immune cell receptors are linked to enzymes called kinases. Kinases covalently attach a
phosphate group to serine, threonine, or tyrosine amino acid residues in a reversible process called
phosphorylation. Phosphate groups can change how a protein interacts with other proteins,
such as by changing enzyme activation states, altering protein binding sites,
or changing how transcription factors behave. Since the addition of a phosphate group
can be reversed by enzymes called phosphatases, which remove phosphate groups, phosphorylation
can act like a molecular light switch, turning certain protein functions on and off as necessary.
Some receptors, such as B and T cell receptors, do not have built-in kinase activity, but once
they and their costimulatory receptors bind their respective ligands, protein kinases can bind to
the intracellular tails of the receptors and begin phosphorylating downstream proteins. Extracellular
ligand binding can cause receptors and coreceptors to physically cluster within the cell membrane,
bringing together the intracellular tails of receptors and coreceptors to
act as docking sites for protein kinases. Activation of kinases is not the only way
for receptor binding to initiate intracellular signaling cascades. Many receptors are coupled to
large or small GTPases, which are enzymes that convert GTP, or guanosine triphosphate, into GDP,
or guanosine diphosphate. These are just like ATP and ADP which we are more familiar with, just with
guanine instead of adenine as the nucleobase. When a G-protein coupled receptor binds its
ligand, a heterotrimeric complex of G proteins binds to the receptor, where heterotrimeric
means comprised of three subunits, at least one of which differs from the other two. In its inactive
state, the G protein heterotrimer is bound to GDP. However, when the G proteins bind the receptor,
GDP is exchanged for GTP, causing the G protein to become activated as long as it is bound to GTP.
The activated G protein subunits then activate multiple pathways throughout the cell, including
motility, proliferation, and changes in gene transcription. Eventually, the GTPase converts
GTP to GDP, rendering the enzyme inactive again. Small GTPases are monomeric, rather than trimeric,
but they function by similar principles as large GTPases. When the enzyme is bound to GDP, it is
in its inactive state. Small G-proteins are often anchored to the inner side of the cell membrane.
When a receptor binds a ligand, adaptor proteins localize to the cytoplasmic tail of the receptor,
recruiting guanine-nucleotide exchange factors (or GEFs) to swap out bound GDP
for GTP, allowing the GTPase to become activated and launch a cell signaling cascade.
Ras, Rac, and Rho are all common small GTPases that can have widespread cell signaling effects.
So, that covers some of the ways that the signal carried by the ligand can then propagate inside a
cell. But what does this signal achieve, exactly? What a cell ultimately does
in response to receptor activation depends on many factors, such as levels of receptor expression and
ligand concentration, as well as which particular combination of receptors were activated,
and in what order. The end of a signaling cascade can lead to a huge range of possible outcomes,
including protein modifications like phosphorylation,
transcription and translation of new proteins, changes in cell adhesion and motility,
phagocytosis, antigen presentation, proliferation, apoptosis,
survival, and release of cytotoxic or microbicidal proteins. We will learn more about these
outcomes where appropriate as we progress through the series. For now, let’s continue
examining immune cell receptors by looking at the types of receptors that can be present.