ACTIVATION AND EFFECTOR FUNCTIONS OF CELL-MEDIATED IMMUNITY AND NK CELLS Choompone Sakonwasun, MD (Hons), FRCPT
Types of Adaptive Immunity
Types of T Cell-mediated Immune Reactions CTLs = cytotoxic T lymphocytes
Activation and Effector Functions of Cell-mediated Immunity The frequency of naïve T cells specific for a given antigen is ~ 1:10 6 too few to fight infection primary goal = replication > 1,000 fold a 50,000 to 100,000-fold increase in the no. of antigen-specific CD8 + T cells may be detected in infected mice the magnitude of clonal expansion of CD4 + T cells is estimated to be 100- to 1,000-fold
Dendritic cells in antigen capture and presentation
T Lymphocyte Activation
Phases of T cell responses APC = antigen-presenting cell IL-2R = interleukin-2 receptor IL-2 = interleukin-2
Functions of different antigen-presenting cells
Recognition of antigen and functions of costimulators paracrine action autocrine action
The major members of the B7 and CD28 families CTLA-4 - cytotoxic T lymphocyte antigen 4 ICOS - inducible costimulator PD-1 - programmed death 1 ITIM - immunoreceptor tyrosine-based inhibition motif ITSM - immunoreceptor tyrosine-based switch motif
Functional Responses of T Lymphocytes Expression of various surface molecules, e.g., CD25 (IL-2Rα), CD40 ligand (CD40L, CD154) IL-2 secretion and IL-2 receptor expression Clonal expansion of T cells Differentiation of CD4 + T cells into T H 1, T H 2, and T H 17 effector cells Differentiation of CD8 + T cells into cytotoxic T lymphocytes Development of memory T cells
Role of CD40 in T cell activation CD40L engages CD40 on APCs and may stimulate the expression of B7 molecules and the secretion of cytokines that activate T cells.
Regulation of IL-2 receptor expression
Biologic actions of IL-2
Clonal expansion of T cells
T H 1, T H 2, and T H 17 subsets of CD4 + helper T cells
Functions of T H 1 cells
Functions of T H 2 cells
Functions of T H 17 cells
Activation of CD8 + T cells Cross presentation
Role of helper T cells in the differentiation of CD8 + T lymphocytes
Mechanisms of CTL-mediated killing of target cells FasL = Fas ligand
Development of memory T cells A. Linear differentiation model B. Branched differentiation model
Activation and Effector Functions of Natural Killer Cells Natural killer (NK) cells A subset of lymphocytes, neither T nor B lymphocytes, constitute 5% to 15% of the mononuclear cells in the blood and spleen Recognize and kill infected cells and certain tumor cells Recognition of target cells depends on Activating and inhibitory receptors ADCC (antibody dependent cell-mediated cytotoxicity)
= recognition of missing self
ADCC (Antibody Dependent Cell-Mediated Cytotoxicity) (CD16)
Activation of NK Cells The major cytokines of the innate immune system that stimulate NK function are IL-12, IL-15, IL-18, and type I interferons Each cytokine enhances the cytotoxic activity of NK cells and the amount of the cytokine IFN-γ the NK cells secrete IL-12 and IL-15 are also important growth factors for NK cells High concentration of IL-2 stimulate the activities of NK cells and may function as adaptive T cellmediated immunity
Effector Functions of NK Cells
Cytokines Proteins secreted by the cells of innate and adaptive immunity mediate many functions of these cells Produced in response to microbes and other antigens Stimulate the growth and differentiation of lymphocytes Activate different effector cells to eliminate microbes and other antigens
Functional Categories of Cytokines 1 Mediators and regulators of innate immunity produced mainly by mononuclear phagocytes in response to bacterial and viral products e.g., TNF-a, IL-1, IL-12, IFN-a, IFNb
Some Cytokines of Innate Immunity 1/2 Cytokine Secreted by Targets and effects Interleukin-1 (IL-1) Tumor necrosis factor-a (TNF-a) Monocytes, macrophages, endothelial cells, epithelial cells Macrophages Endothelial cells : activation (inflammation, coagulation) Hypothalamus : fever Liver : synthesis of acute-phase proteins Endothelial cells : activation (inflammation, coagulation) Neutrophils : activation Hypothalamus : fever Liver : synthesis of acute-phase proteins Muscle, fat : catabolism Many cell types : apoptosis
Some Cytokines of Innate Immunity 2/2 Cytokine Secreted by Targets and effects Interleukin-12 (IL- 12) Interleukin-6 (IL-6) Type I IFN (IFN-a, IFN-b) Macrophages, dendritic cells Macrophages, endothelial cells IFN-a : macrophages IFN-b : fibroblasts T cells : T H 1 differentiation NK cells and T cells : IFN-g synthesis, increased cytolytic activity Liver : synthesis of acute-phase proteins B cells : proliferation and antibody secretion All cells : antiviral state, increased class I MHC expression NK cells : activation
Functional Categories of Cytokines 2 Mediators and regulators of adaptive immunity produced mainly by T lymphocytes in response to recognition of foreign antigens e.g., IL-2, IL-4, IL-5, IFN-g
Some Cytokines of Adaptive Immunity 1/2 Cytokine Secreted by Targets and effects Interleukin-2 (IL-2) T cells T cells : proliferation, increased cytokine synthesis, maintenance of functional regulatory T cells NK cells : proliferation, activation B cells : proliferation Interleukin-4 (IL-4) T H 2 cells, mast cells B cells : isotype switching to IgE T cells : T H 2 differentiation, proliferation Macrophages : inhibition of IFN-g-mediated activation Interleukin-5 (IL-5) T H 2 cells Eosinophils : activation, increased production
Some Cytokines of Adaptive Immunity 2/2 Cytokine Secreted by Targets and effects Interleukin-13 (IL-13) T H 2 cells, basophils, eosinophils, NKT cells B cells : isotype switching to IgE Macrophages : tissue repair and fibrosis, inhibition of IFN-g-mediated activation Airway epithelial cells : mucus production Interleukin-17 (IL-17) T H 17 cells Leukocytes and tissue cells : production of chemokines, inflammatory cytokines, e.g., TNF, IL-1, IL-6 and antimicrobial peptides Interleukin-22 (IL-22) T H 17 cells, NK cells Epithelial tissues : production of antimicrobial peptides, promotio of epithelial barrier functions Interferon-g (IFN-g) T cells (T H 1, CD8 + T cells), NK cells Macrophages : activation Various cells : increased expression of class I and class II MHC molecules, increased antigen processing and presentation to T cells B cells : isotype switching to IgG
Functional Categories of Cytokines 3 Stimulators of hematopoiesis produced by bone marrow stromal cells, leukocytes, and other cells stimulate the growth and differentiation of immature leukocytes e.g., IL-3, GM-CSF (granulocyte-macrophage colony-stimulating factor)