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.