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Effector Mechanisms of Cell Mediated Immunity Eradication of Intracellular Microbes

The effector phase of cell-mediated immunity is carried out by T lymphocytes, and antibodies play no role in eradicating infections by microbes that are living inside host cells.

Types of Cell-Mediated Immunity two types: CD4* T cells activate phagocytes to destroy microbes residing in the vesicles of these phagocytes, and CD8* T cells kill any cell containing microbes or microbial proteins in the cytoplasm Pathogenic microbes that infect and survive inside host cells include A) many bacteria and some protozoa ingested by phagocytes but resist the killing mechanisms of these phagocytes and live in vesicles or cytoplasm and

B) viruses that infect phagocytic and nonphagocytic cells and live in the cytoplasm of these cells . Phagocytes at these sites that have ingested the microbes into intracellular vesicles display peptide fragments of microbial proteins attached to class II MHC molecules for recognition by effector T cells of the CD4+ subset. Peptide antigens derived from microbes living in the cytoplasm of infected cells are displayed by class 1 MHC molecules for recognition by CD8+ effector T cells. Antigen recognition by the effector T cells then activates these cells to perform their task of eliminating the infectious pathogens. Thus, in cell-mediated immunity, T cells recognize protein antigens at two stages: naive T cells recognize antigens in lymphoid tissues and respond by proliferating and by differentiating into effector cells, and effector T cells recognize the same antigens anywhere in the body and respond by eliminating these microbes .

Migration of Effector T Lymphocytes to Sites of Infection


Effector T cells express high molecules(adhesion molecules) bind to ligands on endothelium because chemoattractant cytokines are produced at the infection site The process of differentiation of nave T lymphocytes into effector cells is accompanied by changes in the profiles of adhesion molecules that are expressed on these cells . T cell adhesion molecules are glycoprotein ligands for E- and P-selectins and the high-affinity forms of the integrins LFA-1 (LFA, leukocyte functionassociated antigen) and VLA-4 (VLA referring to very late activation molecules, because they appear later than LFA-1 during the course of T cell activation).

at the site of infection


one of the innate immune responses to the infection is the secretion of cytokines

by macrophages responding to the pathogen Two of these macrophage-derived cytokines,


tumor necrosis factor (TNF) and interleukin-1 (IL-1), act on the endothelial cells of small blood vessels adjacent to the infection site stimulate

to increase expression of E- and P-selectins as well as ligands for integrins, especially ICAM-1 (intercellular adhesion molecule-1, the ligand for LFA-1) and VCAM-1 (vascular cell adhesion molecule-1, the ligand for the VLA-4 integrin) Effector T cells that are passing through the blood vessels at the infection site bind weakly to the selectins and roll along the endothelial surface.

When the integrins of these effector T cells encounter their ligands on the endothelium, the T cells bind firmly to the endothelium and begin the process of migrating out of the blood vessels to the site of infection. Essentially the same molecular interactions are responsible for the migration of other leukocytes, such as neutrophils and monocytes, to sites of infection. On activation, T cells not only increase the expression of the adhesion molecules that enable them to bind to vessels at sites of infection but also lose expression of L-selectin, a molecule that mediates naive T cell migration into lymph nodes. Therefore, activated T cells tend to stay out of normal lymph nodes. The principal function of chemokines is to attract and stimulate the motility of leukocytes. Chemokines are often displayed on endothelial cells bound to cell surface proteoglycans, thus providing a high local concentration near the site of infection. Chemokines are produced at the extravascular infection site by leukocytes that are reacting to the infectious microbe, and this creates a concentration gradient of chemokines toward the infection. the concentration gradient draws the T cells through the vessel wall into the site of infection. Thus, circulating effector T lymphocytes migrate, or "home," to sites of infection and become concentrated at these sites.

Effector Functions of CD4+ T Lymphocytes


CD4* T lymphocytes of the TH1 subset

activate
macrophages that have phagocytosed microbes, The ability of T cells to activate macrophages is dependent on antigen recognition, accounting for the specificity of the reaction. T Cell-Mediated Macrophage Activation Effector T lymphocytes of the TH1 subset that recognize macrophage-associated antigens activate the macrophages by CD40 ligand-CD40 interactions and by secreting the macrophage-activating cytokine interferon-y (IFN-y) trigger biochemical signaling pathways lead to the production of several transcription factors turn on the transcription of genes that encode

lysosomal proteases and enzymes


stimulate

the synthesis of microbicidal reactive oxygen intermediates and nitric oxide

Macrophages that have phagocytosed microbes produce cytokine IL-12.

Stimulates
the differentiation of naive CD4+ T cells to the TH1 subset,

produces
IFN-y on encountering macrophage-associated microbial antigens

activates
the phagocytes to kill the ingested microbes, thus completing the circle.

Elimination of Microbes by Activated Macrophages Macrophage activation leads to the expression of enzymes that catalyze the production of microbicidal substances in phagosomes and phagolysosomes . the major microbicidal substances produced in the lysosomes of macrophages are reactive oxygen intermediates (ROls), nitric oxide (NO), and proteolytic enzymes. Cell-mediated immunity is critical for host defense in two situations: 1. when macrophages are not activated by the microbes themselves (i.e., when innate immunity is ineffective) and 2. when pathogenic microbes have evolved to resist the defense mechanisms of innate immunity. In these situations, the additional macrophage activation by T cells changes the balance between microbes and host defense in favor of the macrophages, thus serving to eradicate intracellular infections.

Role of TH2 Cells in Cell-Mediated Immunity The TH2 subset of CD4* T lymphocytes

stimulates
eosinophil-rich inflammation differentiated TH2 cells recognize antigens

produce
the cytokines IL-4 and IL-5 IL-4 IL-5

Stimulates
production of IgE antibody, eosinophils.

activates

This reaction is important for defense against helminthic infections, because eosinophils bind to IgEcoated helminths and the helminths are killed by the granule proteins of eosinophils. Several cytokines produced by TH2 cells, including IL-4, IL-10, and IL-13, also inhibit macrophage activation. Because of this action, TH2 cells may serve to terminate TH1-mediated DTH reactions and thus limit the tissue injury that often accompanies TH1 cellmediated protective immunity. The relative activation of TH1 and TH2 cells in response to an infectious microbe may determine the outcome of the infection .

Effector Functions of CD8+ Cytolytic T Lymphocytes Antigen recognition by effector CTLs results in the activation of signal transduction pathways that lead to the exocytosis of the contents of the CTL's granules to the region of contact with the targets. CTLs kill target cells mainly as a result of their granule contents creating pores in target cell membranes and introducing into the target cells substances that induce DNA fragmentation and apoptosis. The pore-forming protein of CTL granules is called perforin. When perforin is secreted from CTLs, it inserts into the target cell membrane and is induced to polymerize by the high concentration of Ca2+ ions present in the extracellular environment. Polymerized perforin forms a pore in the target cell membrane. At the same time the CTLs secrete granule enzymes called granzymes, which enter target cells through the perforin pores or by binding to receptors on target cell membranes followed by endocytosis. Granzymes cleave and thereby activate enzymes called caspases that are present in the cytoplasm of the target cells, and the active caspases induce apoptosis. (Caspasesare so named because they are cysteine proteases that cleave proteins at aspartic acid residues; their major function is to induce apoptosis.) Activated CTLs also express a membrane protein called Fas ligand, which binds to a death-inducing receptor, called Fas (CD95), on target cells. Engagement of Fas activates caspases and induces target cell apoptosis; this pathway of CTL killing does not require granule exocytosis and is probably a minor pathway. The net result of these effector mechanisms of CTLs is that the infected cells are killed. Cells that have undergone apoptosis are rapidly phagocytosed and eliminated. The mechanisms that induce fragmentation of target cell DNA, which is the hallmark of apoptosis, may also break down the DNA of microbes living inside the infected cells.

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