Cell‐Mediated Immunity Protects Against Intracellular Organisms
The term cell‐mediated immunity is used to describe the responses of T‐cells, particularly with respect to the ability of some types of T‐helper cells to activate macrophages and the ability of cytotoxic T‐lymphocytes to directly kill infected cells. Many microorganisms live inside host cells where it is usually impossible for humoral antibody to reach them. Obligate intracellular pathogens such as viruses have to replicate inside cells; facultative intracellular pathogens such as Mycobacterium and Leishmania can replicate within cells, particularly macrophages, but do not have to; they like the intracellular life because of the protection it affords. The T‐cells are specialized to operate against cells bearing intracellular organisms.
Their T‐cell receptor (TCR) for antigen, which is different from the antibody molecule used by B‐lymphocytes, does not directly recognize intact antigen. Instead it recognizes antigen that is first processed by the cell in which it is located and then subsequently presented to the T‐cell. This rather more convoluted mechanism required for antigen recognition is necessary in order that the T‐cell sees antigen in association with a cell, rather than non‐cell‐associated antigens such as extracellular bacteria that can be dealt with by antibody. Protein antigens within cells are chewed up by intracellular proteases to generate short peptides. These peptides then need to be taken to the cell surface in order for them to be recognized by the TCR on the T‐cells. It is highly unlikely that, if unaccompanied, the peptides would stay on the cell surface. Without a transmembrane sequence they would simply fall off the surface of the cell and float away – not much use if the T‐cell needs to attach to the particular cell that is infected. An important group of molecules known as the major histocompatibility complex (MHC), identified originally through their ability to evoke powerful transplantation reactions in other members of the same species, carry out the function of transporting the peptides to the cell surface and then displaying them to the TCR on T‐cells. Most T‐cells thus recognize peptide + MHC rather than the intact native antigen recognized by B‐cells.
In general, cytotoxic T‐cells recognize peptides presented by the MHC class I molecules that are present on virtually all nucleated cells in the body. In contrast, helper and regulatory T‐cells usually recognize peptides presented by the MHC class II molecules that are, in addition to MHC class I molecules, present on so‐called “professional antigen‐presenting cells”: the interdigitating dendritic cell, the macrophage and the B‐lymphocyte. Naive (virgin) T‐cells (i.e., those that have not previously encountered their antigen) must be shown the peptide antigen and MHC by the most powerful type of antigen‐presenting cell, the interdigitating dendritic cell, before they can be activated. However, once primed, T‐cells can be activated by peptide antigen and MHC present on the surface of macrophages (or B‐cells) as we shall now see.
Cytokine‐producing T‐cells help macrophages to kill intracellular pathogens
Organisms that are able to survive inside macrophages do so through their ability to subvert the innate killing mechanisms of the phagocyte. Nonetheless, they mostly cannot prevent the macrophage from processing small antigenic fragments (possibly of organisms that have spontaneously died) and placing them on the host cell surface. T‐helper cells, if primed to that antigen, will recognize and bind to the combination of antigen peptide with class II MHC molecules on the macrophage surface and produce a variety of soluble factors termed cytokines. Some T‐cell cytokines help B‐cells to make antibodies, while others such as interferon‐γ (IFNγ) serve as macrophage activating factors that switch on the previously subverted microbicidal mechanisms of the macrophage and thereby bring about the death of the intracellular microorganisms (Figure 2.14).
Using acquired immunity to deal with virally infected cells
We have already discussed the advantage to the host of killing virally infected cells before the virus begins to replicate and have seen that NK cells can carry out a cytotoxic function via their activating receptors (Figure 2.15a and Table 4.3). These receptors inherently have a limited range of specificities. However, NK cells also possess receptors for the constant (Fc) part of the antibody molecule (as discussed earlier with regard to phagocytic cells). This situation enables their range of potential targets to be enormously expanded because the Fc receptors can recognize virus‐specific antibody coating the target cell if any intact viral antigens are present on the surface of the infected cell. Thus antibodies generated by the acquired immune response will bring the NK cell very close to the target by forming a bridge, and the NK cell being activated by the complexed antibody molecules is able to kill the virally infected cell by its extracellular mechanisms (Figure 2.15b). This system is termed antibody‐dependent cellular cytotoxicity (ADCC). However, as previously mentioned a subset of T‐cells with cytotoxic capabilities also exists. Like the T‐helpers, these cells have a very wide range of antigen specificities because they clonally express a large number of different TCRs. Like the T‐helper cell, the cytotoxic T‐cells recognize fragments of protein antigens (peptides) in association with a cell marker, in this case the class I MHC molecule (Figure 2.15c). Through this recognition of surface antigen, the cytotoxic cell comes into intimate contact with its target and administers the “kiss of apoptotic death.” It also releases IFNγ that will help to reduce the spread of virus to adjacent cells, particularly in cases w re the virus itself may prove to be a weak inducer of IFNα or Thus both T‐ and B‐cells provide specific acquired immunity with a variety of mechanisms, which in most cases operate to extend the range of effectiveness of innate immunity and confer the valuable advantage that a first infection prepares us to withstand further contact with the same infectious organism. The defining characteristic of the acquired response is that it is mediated by lymphocytes, which in contrast to the cells of the innate response are highly antigen specific and exhibit strong immunological memory. It is, however, worth noting two important points at this juncture. First, the innate and acquired responses usually work together to defeat the pathogen and, second, that these two systems merge into one another, with some cell types having characteristics that bridge both kinds of response.