micr 304 immunology & serology
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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
Innate Adaptive
Cells PhagocytesEpithelial Cells
NK Cells
Lymphocytes(B-Ly, T-Ly)
Defense Effector Molecules
ComplementAntimicrobial (Poly)PeptidesAntimicrobial
lipids?
Antibodies
Lymphoid Cell Lineage
NaïveLymphocytes
EffectorLymphocytes
IL15IL2, IL7
NK cells
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
Infections with Documented NK Cell Mediated Defense Herpes simplex virus
Cutaneous leishmaniosis (“Bhagdad Sore”)
Cytomegalovirus (CMV)
Killing of Tumor Cells by NK Cells in vitro
Tumor Cell
NK-Cell
t0
t60
NK Cells are an Early Component of Host Defense against Viral
Infections
Virus titer
levels Virus titer decreases
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
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
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
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
NK Cell Activation and Inhibition
NK and normal cell:Inhibition > activation
NK and abnormal cell:Activation uninhibited
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
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
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.
Active LearningBoth neutrophils and NK cells can recognize their
target cells through antibodies. In what are their responses to the target cells
different?
AdaptiveImmunity
Lymphocytes• Mediate adaptive immune responses
+
Specific antigen recognition
Clonal proliferationm
Memory
mm
mm
mm
Lymphocyte DevelopmentLymphoidProgenitor
Helper Cytotoxic RegulatoryNK-Cells
Plasmacell
B-Lymphoblast
Thymocyte
T-Lymphoblast
Prolymphocyte
B-LymphocyteT lymphocyte
IL2, IL7 IL15
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)
Lymphocytes Monitor the Body
Dendritic Cells Initiate Adaptive Immune
Responses
Clonal Expansion ofActivated Lymphocytes
From Antigen to Response• Specific antigen
recognition• Common signal
transduction
nucleus
Reaction
General Principle ofAntigen Receptors
variableconstant
Cytoplasmic tail
ReceptorSignal
transducer
Cytoplasmic tail
Intracellular cascade of signal
transduction
Each Lymphocyte Carries only One Type of Receptor
• “Billions of lymphocytes collectively carry millions of antigens”
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.
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
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