Key Concepts Cytokines and Immune Cell Subsets PDF

**Key concepts covered in the Lecture Cytokines and Immune cell subsets (Dr. Othy). Refer to the slides for details.** - The cells that perform the most effector functions of innate and adaptive immunity are phagocytes (including neutrophils and macrophages), mast cells, basophils, eosino...

**Key concepts covered in the Lecture Cytokines and Immune cell subsets (Dr. Othy). Refer to the slides for details.** - The cells that perform the most effector functions of innate and adaptive immunity are phagocytes (including neutrophils and macrophages), mast cells, basophils, eosinophils, dendritic cells, and natural killer (NK) cells, and lymphocytes. - Many surface molecules are differentially expressed on distinct types and subsets of immune cells, and these are named according to the CD nomenclature. - Neutrophils, the most abundant blood leukocyte with a distinctive multilobed segmented nucleus and abundant cytoplasmic lysosomal granules, are rapidly recruited to infection and tissue injury sites, where they perform phagocytic and microbial killing functions. - Tissue-resident macrophages are sentinel cells that detect microbes and alert the immune system and may perform other specialized functions in different tissues, such as the lung, spleen, and liver. - Monocytes are circulating phagocytes that are recruited to sites of tissue infection and injury, where they rapidly differentiate into macrophages that ingest and kill microbes and dead host cells and secrete cytokines and chemokines that promote the recruitment of leukocytes from the blood and initiate the repair of damaged tissues. - Dendritic cells (DCs) are bone marrow-derived cells with extended cytoplasmic processes that are present in most body tissues and function as innate sentinel cells and antigen-presenting cells (APCs) uniquely capable of activating naive T lymphocytes. Different subsets of DCs have different functions in innate and adaptive immunity. - B and T lymphocytes express highly diverse and specific antigen receptors and are responsible for the specificity and memory of adaptive immune responses. - Both B and T lymphocytes arise from a common precursor in the bone marrow. B cell development proceeds in the bone marrow, whereas T cell precursors migrate to and mature in the thymus. After maturing, B and T cells leave the bone marrow or thymus, enter the circulation, and populate peripheral lymphoid organs. - Naive B and T cells are mature lymphocytes that have not been previously stimulated by antigen. When they encounter antigens, they proliferate and differentiate into effector lymphocytes that have functions in protective immune responses. Effector B lymphocytes are antibody-secreting plasma cells. Effector T cells include cytokine-secreting CD4+ helper T cells and CD8+ CTLs. - Some of the progeny of antigen-activated B and T lymphocytes differentiate into memory cells that survive for long periods in a quiescent state. These memory cells are responsible for the rapid and enhanced responses to subsequent exposures to antigens. - Cell-mediated immunity is the adaptive immune response stimulated by microbes inside host cells. It is mediated by T lymphocytes and can be transferred from immunized to naive individuals by T cells and not by antibodies. - T cells of the CD8+ subset proliferate and differentiate into cytotoxic T lymphocytes (CTLs), which express cytotoxic granules and can kill infected cells. - The differentiation of CD8+ T cells into functional CTLs and memory cells requires recognition of antigen presented by dendritic cells, signals from CD4+ helper T cells in some situations, costimulation, and cytokines. Differentiation to CTLs involves the acquisition of the machinery to kill target cells and is driven by various transcription factors. - CD8+ CTLs kill cells that express peptides derived from cytosolic antigens (e.g., viral antigens) that are presented in association with class I MHC molecules. CTL-mediated killing is mainly the result of exocytosis of secretory granules that contain granzymes and perforin. Perforin facilitates granzyme entry into the cytoplasm of target cells, and granzymes initiate the process of apoptosis. Another granule protein, granulysin, destroys some intracellular bacteria and fungi. - CD8+ T cells also secrete interferon-γ and thus may participate in defense against phagocytosed microbes and in delayed-type hypersensitivity reactions. - Naive CD4+ T lymphocytes may differentiate into different types of specialized effector T cells, including: Th1 cells that secrete interferon-γ (IFN-γ), which mediate defense against intracellular microbes; Th2 cells that secrete interleukin-4 (IL-4) and IL-5, which favor IgE- and eosinophil/mast cell--mediated immune reactions against helminths; or Th17 cells, which promote inflammation and mediate defense against extracellular fungi and bacteria. - The differentiation of naive CD4+ T cells into subsets of helper T cells is induced by cytokines produced by antigen-presenting cells, by the T cells themselves, and by other cells. The differentiation program is governed by transcription factors that promote cytokine gene expression in the T cells and epigenetic changes in cytokine gene loci, which may be associated with stable commitment to a particular subset. Each subset produces cytokines that increase its own development and inhibit the development of the other subsets, thus leading to increasing polarization of the response. - Activated helper T cells express CD40 ligand (CD40L), which engages CD40 on the B cells, and the T cells secrete cytokines that bind to cytokine receptors on the B cells. The combination of CD40 and cytokine signals stimulates B cell proliferation and differentiation. - Some activated helper T cells differentiate into specialized T follicular helper (Tfh) cells that express high levels of inducible costimulator (ICOS) and CXCR5 and secrete interleukin-21 (IL-21). Tfh cells and antigen-activated B cells migrate into the follicle, and Tfh cells activate these specific B cells to initiate the formation of germinal centers. The late events in T cell--dependent antibody responses, including additional isotype switching, somatic mutation, affinity maturation, generation of memory B cells, and induction of long-lived plasma cells, take place within germinal centers. - Th1 cells recognize antigens of microbes that have been ingested by phagocytes and activate the phagocytes to kill the microbes. The activation of macrophages by Th1 cells is mediated by IFN-γ and CD40L-CD40 interactions. Activated macrophages kill phagocytosed microbes ingested into phagolysosomes by the actions of reactive oxygen and nitrogen species and enzymes (called classical macrophage activation). Activated macrophages also stimulate inflammation and can damage tissues. - Th2 cells recognize antigens produced by helminths and other microbes, as well as environmental antigens associated with allergies. IL-4 promotes B cell isotype switching and production of IgE, which may cause mast cell degranulation and inflammation. IL-5 secreted by activated Th2 cells activates eosinophils to release granule contents that destroy helminths but may also damage host tissues. IL-4 and IL-13 together provide protection at epithelial barriers and induce an alternative form of macrophage activation that generates macrophages that control inflammation and mediate tissue repair and fibrosis. - Th17 cells stimulate neutrophil-rich inflammatory responses that eradicate extracellular bacteria and fungi and maintain the integrity of epithelia. Th17 cells also may be important in mediating tissue damage in autoimmune diseases. - γδ T cells, natural killer T cells, and mucosa-associated invariant T cells are T cells that express receptors of limited diversity and recognize various antigens without a requirement for major histocompatibility complex--associated presentation. These cells produce cytokines and may contribute to host defense and inflammatory diseases.