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The Innate Immune System Instigates Adaptive Immunity


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 cell morphology. (a) Phase‐contrast image of an unstained dendritic cell with characteristic “dendron tree.”

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.

Dendritic cell maturation is induced by PAMPs and other signs of infection. (a) Immature dendritic cells (DCs) undergo maturation and become equipped to present antigen and provide co‐stimulatory signals upon activation by a pathogen‐associated molecular patterns (PAMPs) (or danger‐associated molecular pattern (DAMP)), as this leads to a dramatic increase in the expression of surface MHC and B7 molecules on the DC. The expression of B7 family proteins is controlled by NFkB, which is activated downstream of many PRRs. Whereas immature DCs are relatively nonmotile, mature DCs are highly motile and migrate to secondary lymphoid tissues to present antigen to T‐cells. (b) Mouse epidermal Langerhans cells (i.e., DCs of the skin) were stained for langerin (green) and MHC class II (red) either before (left) or after maturation (right). Note that before DC maturation MHC class II (red) is present intracellularly, whereas after maturation it is readily detected on the cell surface.

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.

Dendritic cells (DCs) present antigen to T‐cells of the adaptive immune system. MHC molecules on DCs function as serving platforms for dismembered proteins (i.e., peptides). T‐cells can only “see” antigen when presented within the cleft of an MHC molecule; this represents signal 1. In addition to presenting antigen to T‐cells in the correct format, DCs also give permission for T‐cells to undergo clonal expansion (i.e., proliferation to increase their numbers) 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.