T lymphocytes injure tissues by either producing cytokines that induce inflammation or directly killing target cells (Fig. 1). Inflammatory reactions are elicited mainly by CD4+ T cells of the Th1 and Th17 subsets. In some T-cell–mediated disorders, the principal mechanism of tissue injury is killing of cells by CD8+ CTLs. The T cells that cause tissue injury may be auto reactive, or they may be specific for foreign protein antigens that are present in or bound to cells or tissues. T-lymphocyte mediated tissue injury may also accompany strong protective immune responses against persistent microbes, especially intracellular microbes that resist eradication by phagocytes and antibodies.
Fig1. Mechanisms of T-cell–mediated diseases. (A) In cytokine-mediated inflammatory reactions, CD4+ T cells (and sometimes CD8+ cells, not shown) respond to tissue antigens by secreting cytokines that stimulate inflammation and activate leukocytes, leading to tissue injury. (B) In some diseases, CD8+ cytotoxic T lymphocytes (CTLs) directly kill tissue cells. APC, Antigen-presenting cell.
A role for T cells in causing a particular immunologic dis ease is suspected largely on the basis of the demonstration of T cells in lesions and the detection of increased levels of cytokines in the blood or tissues that may be derived from T cells. Animal models have been useful for elucidating the pathogenesis of these disorders. Single-cell transcriptional profiling is now being used to define the cell types in inflammatory lesions, with the hope that this will provide new insights into pathogenesis.
Diseases Caused by Cytokine-Mediated Inflammation
In immune-mediated inflammation, Th1 and Th17 cells secrete cytokines that recruit and activate leukocytes. Recall that inflammation is a major defense reaction of innate immunity. When T cells are involved, the inflammation becomes more severe and chronic because T cells induce the production of potent inflammatory mediators for prolonged periods. IL-17, produced by Th17 cells, promotes neutrophil recruitment; interferon-γ (IFN-γ), produced by Th1 cells, activates macrophages; and tumor necrosis factor (TNF) and chemokines, produced by T lymphocytes and cells of innate immunity (such as dendritic cells [DCs] and macrophages), are involved in the recruitment and activation of many types of leukocytes. (Th2 cytokines induce eosinophil-rich allergic inflammation [type I hypersensitivity] and are discussed in Chapter 20.) Although we emphasize CD4+ Th1 and Th17 cells as the sources of cytokines, in lesions many other cells may produce the same cytokines. For instance, in psoriasis, γδ T cells also produce IL-17, and innate lymphoid cells (ILCs) in tissues may produce many of the same cytokines as do T cells.
Tissue injury results from the products of the recruited and activated neutrophils and macrophages, such as lysosomal enzymes and reactive oxygen species. Cytokines produced by activated lymphocytes and macrophages stimulate more leukocyte recruitment and inflammation, thus propagating the dam age (see Chapter 10). Vascular endothelial cells in the lesions may express increased levels of cytokine-regulated surface proteins, such as adhesion molecules and major histocompatibility complex (MHC) class II molecules. The inflammation associated with T-cell–mediated diseases is typically chronic, but bouts of acute inflammation may be superimposed on a back ground of chronic inflammation. Delayed-type hypersensitivity (DTH) is an example of such inflammatory reactions and is described later. Chronic inflammatory reactions often produce fibrosis as a result of the secretion of cytokines and growth fac tors by the macrophages and T cells that activate fibroblasts and stimulate collagen production.
Many organ-specific autoimmune diseases are caused by the activation of autoreactive T cells by self antigens, leading to cytokine release and inflammation. This is thought to be the major mechanism underlying rheumatoid arthritis, multiple sclerosis (MS), type 1 diabetes, psoriasis, and other autoimmune diseases (Table 1). Some of these diseases are described in more detail at the end of this chapter.
Table1. T-Cell–Mediated Diseases
T-cell responses specific for microbes and other foreign antigens may also lead to inflammation and tissue injury. Intracellular bacteria such as Mycobacterium tuberculosis induce strong T-cell and macrophage responses that result in granulomatous inflammation and fibrosis (described later); the inflammation and fibrosis may cause extensive tissue destruction and functional impairment, typically in the lungs. Tuberculosis is a good example of an infectious disease in which tissue injury is mainly due to the host immune response. T-cell responses against intestinal bacteria are thought to under lie some forms of IBD.
A variety of skin diseases, called contact sensitivity, result from topical exposure to chemicals and environmental anti gens. These disorders are caused by inflammatory reactions that are likely triggered by neoantigens formed by the binding of the chemicals to self proteins, including MHC molecules. Both CD4+ and CD8+ T cells may be the source of cytokines in contact sensitivity reactions. Examples of contact sensitivity (called contact dermatitis by clinicians) include rashes induced by poison ivy and poison oak (in which T cells react against self proteins that are modified by plant chemicals called urushiols); by contact with metals (nickel and beryllium, which may bind to MHC molecules and alter their structure) and a variety of chemicals, such as thiuram, which is used in the manufacture of latex gloves; and by therapeutic drugs.
Delayed-Type Hypersensitivity
Delayed-type hypersensitivity (DTH) is an injurious cytokine mediated inflammatory reaction resulting from the activation of T cells, particularly CD4+ T cells. The reaction is called delayed because it typically develops 24 to 48 hours after antigen challenge in a previously immunized (sensitized) individual, in contrast to immediate hypersensitivity (allergic) reactions, which develop within minutes.
In the classic animal model of DTH, a guinea pig was first immunized by the administration of a protein antigen in adjuvant; this step is called sensitization. About 2 weeks later, the animal was challenged subcutaneously with the same antigen, and the subsequent reaction was analyzed; this step is called the elicitation phase. Humans may be sensitized for DTH reactions by microbial infection, by contact sensitization with chemicals and environmental antigens, or by intradermal or subcutaneous injection of protein antigens (Fig.2). Subsequent exposure to the same antigen (called challenge) elicits the reaction. For example, purified protein derivative (PPD), a protein antigen of M. tuberculosis, elicits a DTH reaction, called the tuberculin reaction, when it is injected into individuals who have been exposed to M. tuberculosis. A positive tuberculin skin test response is a widely used clinical indicator of previous or active tuberculosis infection.
Fig2. Delayed-type hypersensitivity (DTH) reaction. Infection or immunization (vaccination) sensitizes an individual, and subsequent challenge with an antigen from the infectious agent elicits a DTH reaction. The reaction is manifested by induration with redness and swelling at the site of the challenge, which peaks at approximately 48 hours. Courtesy Dr. J. Faix, Department of Pathology, Stanford University School of Medicine, Palo Alto, California.
The characteristic response of DTH evolves over 24 to 48 hours. About 4 hours after the injection of an antigen in a sensitized individual, neutrophils accumulate around the post capillary venules at the injection site. By about 12 hours, the injection site becomes infiltrated by T cells and blood monocytes, also organized in a perivenular distribution (Fig. 3). The endothelial cells lining these venules become enlarged and show increased organelles, and the vessels leak plasma mac romolecules. Fibrinogen escapes from the blood vessels into the surrounding tissues, where it is converted into fibrin. The deposition of fibrin, edema, and the accumulation of T cells and monocytes within the extravascular tissue space around the injection site cause the tissue to swell and become firm (indurated). Induration, a diagnostic feature of DTH, is detectable by about 18 hours after the injection of antigen and is maximal by 24 to 48 hours. In clinical practice, loss of DTH responses to universally encountered antigens (e.g., Candida antigens) is an indication of deficient T-cell function, a condition known as anergy. (This general loss of immune responsiveness is different from lymphocyte anergy, a mechanism for maintaining tolerance to specific antigens.)
Fig3. Morphology of a delayed-type hypersensitivity (DTH) reaction. (A) Histopathologic examination of the reaction in skin illustrated in Fig. 2 shows perivascular mononuclear cell infiltrates in the dermis. At higher magnification (not shown), the infiltrate is seen to consist of activated lymphocytes and macrophages surrounding small blood vessels in which the endothelial cells are also activated. (B) Immunohistochemical staining demonstrates the presence of many CD4+ T lymphocytes. Courtesy Dr. J. Faix, Department of Pathology, Stanford University School of Medicine, Palo Alto, California.
Although DTH has traditionally been considered a Th1 mediated injurious reaction, other T cells may contribute to the inflammation. In some DTH lesions, neutrophils are prominent, suggesting the involvement of Th17 cells. In infections by some helminthic parasites, reactions against the parasite eggs elicit DTH with a strong component of eosinophils. In these cases, a role for Th2 cytokines has been demonstrated. CD8+ T cells also produce IFN-γ and contribute to DTH reactions, especially in the skin.
Chronic DTH reactions and fibrosis can develop if a Th1 response to an infection activates macrophages but fails to eliminate phagocytosed microbes. With some infections, the reaction produces nodules of inflammatory tissue called granulomas (Fig. 4A). Chronic DTH, as exemplified by granulomatous inflammation, is caused by prolonged cytokine signals (see Fig. 4B). In such reactions, the activated T cells and macro phages continue to produce cytokines and growth factors, which amplify the reactions of both cell types and progressively modify the local tissue environment by activating fibroblasts that lay down collagen. The result is a cycle of tissue injury and chronic inflammation followed by replacement with connective tissue (fibrosis). In chronic DTH reactions, activated macrophages also respond to persistent cytokine signals by increasing cytoplasm and cytoplasmic organelles. Histologically, these macro phages may resemble skin epithelial cells, because of which they are sometimes called epithelioid cells. Activated macrophages may fuse to form multinucleate giant cells. Granulomatous inflammation is an attempt to contain the infection but is also the cause of significant tissue injury and functional impairment. This type of inflammation is a characteristic response to some persistent microbes, such as M. tuberculosis, and some fungi. Much of the respiratory difficulty associated with tuberculosis or chronic fungal infection of the lungs is caused by replacement of normal lung tissue with fibrotic tissue and is not directly attributable to the microbes.
Fig4. Granulomatous inflammation. (A) Lymph node from a patient with tuberculosis containing granulomas with activated macrophages, multinucleate giant cells, and lymphocytes. In some granulomas, there may be a central area of necrosis (not shown). Immunohistochemical studies would identify the lymphocytes as mainly T cells. (B) Mechanisms of granuloma formation. Cytokines are involved in the generation of Th1 cells, activation of macrophages, and recruitment of leukocytes. Prolonged reactions of this type lead to the formation of granulomas. APC, Antigen-presenting cell; IFN-γ, interferon-γ; TNF, tumor necrosis factor.
Diseases Caused by Cytotoxic T Lymphocytes
Cytotoxic T-lymphocyte (CTL) responses to viral infection can lead to tissue injury by killing infected cells, even if the virus itself has little cytopathic effect. The principal physiologic function of CTLs is to eliminate intracellular microbes, primarily viruses, by killing infected cells. Some viruses directly injure infected cells and are said to be cytopathic, whereas others are not. Because CTLs cannot distinguish between cytopathic and noncytopathic viruses, they kill virus-infected cells regardless of whether the infection itself is harmful to the host. Examples of viral infections in which the lesions are mainly due to the host CTL response and not the virus itself include lymphocytic choriomeningitis in mice and certain forms of viral hepatitis in humans.
CTLs may contribute to tissue injury in autoimmune disorders in which destruction of particular host cells is a prominent component, such as type 1 diabetes, in which insulin-producing β cells in pancreatic islets are destroyed. CTLs also cause injury to organ allografts during rejection responses.
