MICR 304 Immunology & Serology Lecture 6 NK Cells, Lymphocytes Chapter 1.4 –1.17; 2.30 – 2.33 Lecture 6 NK Cells, Lymphocytes Chapter 1.4 –1.17; 2.30 –

MICR 304 Immunology &

Serology

MICR 304 Immunology &

Serology

Lecture 6 NK Cells, Lymphocytes

Chapter 1.4 –1.17; 2.30 – 2.33

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 Learning

Both 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 Development

LymphoidProgenitor

Helper Cytotoxic RegulatoryNK-Cells

Plasmacell

B-Lymphoblast

Thymocyte

T-Lymphoblast

Prolymphocyte

B-Lymphocyte

T 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

variable

constant

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