Cell-Mediated Immune Responses
Not all adaptive immunity involves antibody; protection against many
important pathogens is mediated by T
lymphocytes and B cells play no part. This type of immunity is often loosely
termed ‘cell-mediated immunity’ (CMI) because, historically, it was not
possible to transfer this immunity from one animal to another simply by
transferring plasma containing antibodies. It was first identified in immunity
to tuberculosis and later found to be also involved in contact sensitivity,
immunity to some viruses, graft rejection, chronic inflammation and tumour
immunity. CMI actually covers at least two different responses: the generation
of specific cytotoxic T cells against intracellular viruses (left half
of figure) and the effect of T cells in increasing the activities of ‘non-specific’ cells such as
macrophages, to enable them to deal more
vigorously with intracellular bacteria and other parasites (right half of
figure). Confusingly, this latter type of response is often referred to as delayed
hypersensitivity, which really only describes a particular kind of
inflammatory tissue damage measured by skin testing. The role of CMI in causing
tissue damage and the rejection of grafts is described in Figs 37 and 39,
respectively.
Similar to the antibody response,
CMI is regulated by various cells and factors (not shown in the figure), the
normal function of which is presumably to limit damaging side effects, but
which in some diseases seriously
impair the protective response (see Fig. 22).
Viruses cannot survive for long outside the cells of
the host, which they replicate in, spread from and sometimes destroy (see Fig.
27).
MHC I Class I MHC molecules (A, B, C in humans, K, D,
L in mouse; see Fig. 11), which are an essential part of the recognition of
viral antigens by the receptor on cytotoxic CD8 T cells (see Figs 12 and 18).
TC The cytotoxic or ‘killer’ T cell with the function of detecting and
destroying virus-infected cells. TC release cytokines such as IFNγ
and TNF-α, which may be important in controlling virus replication in cells
without killing their targets. TC are also important for controlling
infections caused by some intracellular bacteria, especially Mycobacterium
tuberculosis.
APC Although class I MHC is present on most cell
types, thus allowing TC to recognize and destroy any virally
infected cells, TC have first to be ‘primed’ by dendritic cells in
the lymph nodes or spleen. Dendritic cells present viral antigens either by
being infected directly, or by picking up fragments of neighbouring infected
cells and loading them on to class I MHC (cross-priming).
TH cells come in many types, and are required for
almost all aspects of the immune response. For most antiviral responses, the TC
response is much more effective and long-lived if the virus also stimulates CD4
TH1 cells, which recognize viral antigens in association with class
II MHC on the antigen-presenting cell. TH1 cells also have an
important role in activating macrophages to become activated and kill intracellular
pathogens (see TH1 and TH2 cells; see Fig. 15). A more
recently described type of TH cell, the TH17 cell, helps
recruit and activate neutrophils. Individuals with defective T17
cells develop life-threatening fungal infections. Many of the functions of TH
are carried out by release of cytokines (especially IL-2 and IFNγ), which act
at short range to activate their target cell (see below and Figs 23 and 24).
Killing Once primed and fully mature, TC
will specifically kill virally infected target cells. Killing occurs in two
stages: binding by the receptor when it recognizes the right combination
of class I MHC antigen plus virus, and Ca2+ dependent lysis of
the target cell. A key feature of all T-cell killing is that it works by
activating the target cell to commit suicide, a process known as apoptosis (or
programmed cell death). Once initiated, this process can continue after the TC
has detached, so that one TC can kill several target cells. Killing
is principally carried out by the secretion of perforins and granzymes.
Per- forins are small pore-forming molecules similar to the terminal complement
lytic complex. Insertion of these molecules into the target cell membrane
allows the entry of granzymes, proteolytic enzymes that activate the caspase
cascade and thus initiate apoptosis. Some TC use an alternative pathway, in
which Fas ligand on the T cell (a molecule belonging to the TNF family)
interacts with Fas receptor on the target, to initiate apoptosis.
Bacteria Certain bacteria, protozoa and fungi, having
been phagocytosed by macrophages (MAC), avoid the normal fate of intracellular
killing (see Fig. 9) and survive, either within the phagolysosome or
free in the cytosol. In the absence of assistance from the T cells this would
result in progressive and incurable infection. Note that the T-helper cells
involved here need to secrete IFNγ and are therefore of the TH1 type. Recent research suggests that vitamin D
is essential for IFNγ to activate macrophages effectively, perhaps explaining
why vitamin D deficiency has been
associated with an increased risk of tuberculosis.
CK Cytokines, a large family of molecules produced
by lymphoid and myeloid cells that regulate the activity of both haemopoietic
and non-haemopoietic cells. Some of the main cytokines involved in cellular
immunity are listed below (for more details see Figs 23 and 24).
1
IL-1: an
unusual cytokine in that it acts systemically through the body, activating the
acute-phase response in liver (see Fig. 7) and increasing body temperature
(fever) via its action on the hypothalamus.
2
IL-2: once
known as T-cell growth factor, IL-2 is important in allow- ing T cells to
proliferate and differentiate into TC. A structurally related cytokine, IL-15,
promotes natural killer (NK) cell differentiation. Another member of the same
family, IL-7, is essential for lymphocyte development (see Fig. 16).
3
IL-12 and
IL-23: two cytokines that share a common α chain; both are produced by
dendritic cells and direct CD4 T cells towards the TH1 and TH17 differentiation pathway, respectively.
4
IL-17: a
more recently identified cytokine that is produced by the TH17 subset of
T-helper cells. It stimulates a strong neutrophil response.
5
MIF
(macrophage migration inhibition factors): a heterogeneous group of molecules,
which by restricting the movement of macro- phages concentrate them in the
vicinity of the T cell.
6
MAF
(macrophage activating factors): increase many macrophage functions, including
intracellular killing and the secretion of various cytotoxic factors able to
kill organisms extracellularly. The most important MAF is IFNγ.
7
TNF-α: an
important cytokine in the regulation of inflammation, via its effect on the
properties of endothelium, causing leucocytes to adhere to the wall of the
blood vessel and migrate into tissues. Like IL-1 it can act systemically, and
if produced in excess can cause ‘wasting’, fever and joint destruction.
8
IL-10 and
TGF-β: in contrast to all the above, which enhance immune responses in various
ways, these two cytokines are important in limiting and slowing down the
cellular immune response, so as to avoid excessive damage to the infected
tissues.
Granuloma Undegradable material (e.g. tubercle bacilli,
streptococ- cal cell walls, talc) may be sequestered in a focus of
concentric macrophages often containing some T cells, eosinophils (EO)
and giant cells, made from the fusion of several macrophages. For the
role of granulomas in chronic inflammation see Fig. 37.
Memory All the T cells involved in CMI can give rise
to memory cells and thus secondary responses of increased effectiveness.
Persistence of memory can apparently occur in the complete absence of antigen,
although memory cells require cytokines such as IL-15 to continue dividing at a
slow rate.
DTH Delayed-type hypersensitivity. The first
evidence for adaptive immunity in tuberculosis was the demonstration (Koch,
1891) that injection of a tubercle antigen ‘tuberculin’ into the skin caused a
swollen red reaction a day or more later. In patients with antibody, the
corresponding reaction would take only hours, whence the terms ‘delayed’ and
‘immediate’ hypersensitivity, respectively. DTH depends on the presence of
T-memory cells; the changes shown in the figure (right-hand side) occur at the
site of injection, together with increased vascular permeability. Thus, DTH is
a useful model of normal CMI and
also a convenient test for T-cell memory.
