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.
