The Innate Immune System Instigates Adaptive Immunity
As we have seen
throughout this chapter, any infectious agent that manages to enter the body
faces a formidable array of defensive weapons, ranging from macrophage‐and
neutrophil‐mediated phagocytosis, to complement‐mediated attack, membrane
perforation by defensins, and digestion by extracellular enzymes. As if all of
this were not enough, the innate immune system also plays a critical role in initiating an immune response
that is uniquely tailored to the ongoing infection. This is achieved by calling
upon cells of the adaptive immune system and instructing these cells in the
nature of the particular antigens that are giving cause for concern. This
function, called antigen presentation, is carried out largely,
but not exclusively, by a cell that has relatively recently come to the fore as
being of critical importance as a conduit between the innate and adaptive
immune systems: the dendritic cell (DC).
Dendritic cells, which
were discovered by Steinman and Cohn in 1973, are produced primarily in the
bone marrow and derive their name from the multiple long membrane projections
or dendrites that these cells possess (Figure 1.43). These cells share a common
progenitor with macrophages, with the result that both macrophages and DCs have
somewhat over-lapping functions. DCs effectively grant permission for T‐cells
of the adaptive immune system to become involved in fighting an
infection. They achieve this by providing such cells with two signals that
are essential for a naive T‐cell (i.e., one that has not
previously been engaged in an immune response) to become activated and to
undergo clonal expansion and differentiation to a fully fledged effector
T‐cell (i.e., capable of mounting immune responses). We will look at
the role of the T‐cell in the immune response in much greater detail in Chapter
8; for now it is sufficient to know that activated T‐cells carry out a range of
functions that reinforce the efforts of the innate immune system, by providing
cytokines to help activate macrophages and attract neutrophils. Some T‐cells
also have functions very similar to NK cells and can detect and kill virally
infected cells, while other T‐cells assist in the production of antibodies, the
functions of which we will deal with in the next chapter.
Dendritic cells provide a conduit between the innate
and adaptive immune systems
Similar to
macrophages, DCs migrate to the tissues where they reside in a quiescent state,
continuously sampling their environment by phagocytosis and pinocytosis. These
cells have been given various names depending on the tissue they are found in;
for example the DCs in the skin are called Langerhans cells. DCs are equipped
with a battery of TLRs and other PRRs and, similar to macrophages, perform a
function as sentinels, waiting and watching for signs of infection or tissue
damage (i.e., engagement of any of their PRRs). However, unlike the macrophage,
DCs do not stand and fight upon PRR engagement but rather take flight to the
nearest lymph node (which acts as a kind of army barracks for lymphocytes) to
carry out a special function, called antigen presentation, which
awakens cells of the adaptive immune system (Figure 1.44 and Figure 1.45). We
will discuss this in much more detail in Chapter 5, but will quickly summarize
events now as it is important that the reader is aware of the central role of
DCs in adaptive
immunity from the outset.
DCs present antigen to T‐cells and provide co‐stimulatory
signals
Whereas cells of the
innate immune system can directly sense non self molecules using their panoply
of PRRs, the T‐lymphocytes of the adaptive immune system need to have antigen
“presented” to them in a special format. Typically this involves protein
antigens becoming internalized and broken down into small peptide fragments by
an antigen‐presenting cell (APC), such as a DC. Antigen
presentation by the DC is achieved via a membrane complex called the major
histocompatibility complex (MHC), which was originally discovered for
its role in graft rejection (hence the unwieldy name). In essence, MHC
molecules function as serving platforms for dismembered proteins and T‐cells
can only “see” antigen when presented within the cleft of an MHC molecule; this
represents signal 1 (Figure 1.45). T‐cells inspect antigen
presented on DCs using their membrane‐borne T‐cell receptors (TCRs),
which are specialized for the recognition of peptide–MHC complexes. Successful
triggering of a TCR results in activation and the acquisition of various
immune‐related functions by the T‐cell (see Chapters 7 and 8). Although DCs are
the most efficient APCs for presenting antigen to T‐cells, macrophages and
B‐cells can also perform this important function.
In addition to
presenting antigen to T‐cells in the correct format, DCs also give permission
for T‐cells to undergo clonal expansion by providing co‐stimulatory
signals in the form of the membrane ligands, B7–1 and B7–2 (also called
CD80/ CD86), that engage with CD28 on the surface of the T‐cell; this
represents signal 2 (Figure 1.45).
Co‐stimulation (i.e.,
signal 2) is not some afterthought on the part of the DC, for if it is absent
the T‐cell refuses to respond in the correct manner and will often kill itself
through programmed cell death (apoptosis). Just to be sure that we are
perfectly clear here, because this is critical for activation of the adaptive
immune system, naive T‐cells require both signal 1 and 2 from an APC to
become successfully activated.
Engagement of PRRs equips DCs to provide
co‐stimulation
Because of the
requirement for signals 1 and 2 for proper T‐cell activation, knowing when to
provide co‐stimulation is a critical feature of the role of an APC. The astute
reader will now be wondering how a DC knows when to provide co‐stimulation, as
this essentially dictates whether the adaptive immune system will be engaged or
not.
Once again, PRRs
provide the key to knowing when the immune system should respond or not. DCs
only become equipped to provide co‐stimulatory signals upon activation by a
PAMP (or DAMP), as this leads to a dramatic increase in the expression of
surface B7 molecules on the DC; the expression of B7 family proteins are also
controlled by NFkB, which is activated downstream of many PRRs. DCs that
present antigen acquired in the absence of PAMP‐mediated stimulation are
overwhelmingly likely to be presenting molecules derived from self and will
therefore fail to provide the proper co‐stimulatory signals required to
activate naive T‐cells (Figure 1.45).
The upshot of all of
this is that the adaptive immune system is heavily reliant on cells of the
innate immune system for the purposes of knowing when to initiate a response
and what to respond to.
