micr 304 immunology & serology
DESCRIPTION
MICR 304 Immunology & Serology. Lecture 6 NK Cells, Lymphocytes Chapter 1.4 –1.17; 2.30 – 2.33. Overview of Today’s Lecture. Lymphoid cell lineage NK cells and their receptors Lymphocytes Principles of cell signaling. Key Players in Immunology. Lymphoid Cell Lineage. Naïve - PowerPoint PPT PresentationTRANSCRIPT
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MICR 304 Immunology & Serology
Lecture 6 NK Cells, Lymphocytes
Chapter 1.4 –1.17; 2.30 – 2.33
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Overview of Today’s Lecture
• Lymphoid cell lineage • NK cells and their receptors• Lymphocytes• Principles of cell signaling
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Key Players in Immunology
Innate Adaptive
Cells PhagocytesEpithelial Cells
NK Cells
Lymphocytes(B-Ly, T-Ly)
Defense Effector Molecules
ComplementAntimicrobial (Poly)PeptidesAntimicrobial
lipids?
Antibodies
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Lymphoid Cell Lineage
NaïveLymphocytes
EffectorLymphocytes
IL15IL2, IL7
NK cells
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NK-Cells Form Part of the Innate Immune System
• Large granular lymphoid cells
• Develop in bone marrow (and maybe in the thymus?)– IL-15 dependent
• Circulate in peripheral blood• Kill infected and tumor cells
– Well documented role in defense against infections with viruses from Herpes family
– Infections with Leishmania and Listeria
– Tumor cells in vitro• Invariant receptors
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Infections with Documented NK Cell Mediated Defense Herpes simplex virus
Cutaneous leishmaniosis (“Bhagdad Sore”)
Cytomegalovirus (CMV)
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Killing of Tumor Cells by NK Cells in vitro
Tumor Cell
NK-Cell
t0
t60
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NK Cells are an Early Component of Host Defense against Viral
Infections
Virus titer
levels Virus titer decreases
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Contributions of NK Cells to Defense against Virus
Infections• NK cells control the initial infection until
adaptive immune system can eliminate the virus
• NK cells are activated by cytokines made by infected cells, macrophages and dendritic cells– INF, IFN, IL12, TNF,
• NK cells begin to kill infected cells• In addition, NK cells secrete IFN
activating macrophages and dendrictic cells, and driving immune response to TH1 type response
• NK-DC cross talk
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How do NK Cells Kill? • Triggered by two mechanisms
– Antibody dependent cytotoxicity– Recognition of altered surface
molecules • Mediated by:
– Perforin• Pore-forming toxin• Permeabilizes target cell membrane
– Granzymes• Enzymes• Induces apoptosis (cell suicide)
– TNF• Apoptosis
Packaged in
Granules
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Antibody Dependent Cellular Cytotoxicity (ADCC)
NK cells recognize antibodies that are bound to target cells through FcIII receptor (CD16)
CD16 is an activating NK cell receptor
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NK Cells Recognize Altered Cell Surface
• Depends on two types of receptors:– Activating (trigger cytotoxicity)
• Direct recognition of changes in cell surface glycoproteins
– Inhibitory • Normal MHC I
• Balance of activating and inhibitory receptor signaling regulates NK cell responses
• In normal cells, inhibitory receptors override activating signals
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NK Cell Activation and Inhibition
NK and normal cell:Inhibition > activation
NK and abnormal cell:Activation uninhibited
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Activating Receptors on NK Cells
• Direct recognition of changes in cell surface glycoprotein
• Short cytoplasmic tail
• Associate with signaling adaptor proteins that initiate activation cascade
• Example: NKG2D– Binds to proteins that
are expressed in cellular stress
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Inhibitory Receptors on NK Cells
• Specific for various MHC I molecules– If MHC I is altered or
down regulated inhibitory receptors do not bind and NK cells become uninhibited
• Long cytoplasmic tail• Associates with
inhibitory phosphatases
• Example: KIR-2DL
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Additonal Roles of NK Cell in our Immune System
• Recent evidence suggests that NK cells contribute to the pathogenesis of hypersensitivity and autoimmune diseases (Bubnoff et al., 2010)– Cytokines released by NK cells
influence disease development.
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Active LearningBoth neutrophils and NK cells can recognize their
target cells through antibodies. In what are their responses to the target cells
different?
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AdaptiveImmunity
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Lymphocytes• Mediate adaptive immune responses
+
Specific antigen recognition
Clonal proliferationm
Memory
mm
mm
mm
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Lymphocyte DevelopmentLymphoidProgenitor
Helper Cytotoxic RegulatoryNK-Cells
Plasmacell
B-Lymphoblast
Thymocyte
T-Lymphoblast
Prolymphocyte
B-LymphocyteT lymphocyte
IL2, IL7 IL15
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Adaptive Immune Responses
• Antibody secretion (B-cells)– To block the invader– To enhance phagocyte and NK cell function
• Activation of effector cells via cytokines (TH cells)– to better fight infection
• Destruction of uncontrollable cells (CTL)– Infection by intracellular pathogens– Tumor cells
• Control of immune response (Regulatory T cells)
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Lymphocytes Monitor the Body
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Dendritic Cells Initiate Adaptive Immune
Responses
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Clonal Expansion ofActivated Lymphocytes
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From Antigen to Response• Specific antigen
recognition• Common signal
transduction
nucleus
Reaction
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General Principle ofAntigen Receptors
variableconstant
Cytoplasmic tail
ReceptorSignal
transducer
Cytoplasmic tail
Intracellular cascade of signal
transduction
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Each Lymphocyte Carries only One Type of Receptor
• “Billions of lymphocytes collectively carry millions of antigens”
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Today’s Take Home Message
• The lymphoid cell lineage gives rise to lymphocyte (IL2 and IL7 dependent) and to NK cells (IL15 dependent)
• NK cells kill infected and tumor cells are the first producers of IFN during an immune response.
• NK cells are regulated by a complex balance of activating and inhibitory receptors.
• Activating receptors like NKG2D recognize new surface molecules produced upon cellular stress. Inhibitory NK cell receptors like KIR-2DL bind to normal MHC I molecules.
• Lymphocytes express antigen specific receptors and unlike other immune cells they undergo clonal expansion and development into memory cells.
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Additional Resources
• Zhou F.(2010) Expression of multiple granzymes by cytotoxic T lymphocyte implies that they activate diverse apoptotic pathways in target cells. Int Rev Immunol. 2010;29(1):38-55.
• von Bubnoff et al. (2010) Natural killer cells in atopic and autoimmune diseases of the skin. J Allergy Clin Immunol. Jan;125(1):60-8.
• http://education.vetmed.vt.edu/curriculum/vm8054/Labs/Lab6/IMAGES/MONOCYTE%20IN%20SMEAR.JPG