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Lymphocyte Effector Functions: Killing. Major Lymphocyte Subpopulations in Peripheral Blood and Selected Effector Functions. B cells T cells. B “Other” CD8 CD4. Ab production Cytotoxicity Help to B cells

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Major Lymphocyte Subpopulations in Peripheral Blood and Selected Effector Functions

B cells T cells

B “Other” CD8 CD4

Ab production Cytotoxicity Help to B cells

Ag presentation Help to CD8 T cells

Cytokine secretion

Antigen Presentation Pathways;

Two Old:

and Two New:

MHC Class I presentation of peptides

MHC Class II presentation of peptides

Cross-priming of exogenous peptides (MHC Class I)

CD1-mediated presentation of glycolipids


How do viruses that don’t infect

“professional APCs” such as dendritic

cells elicit a primary immune response?

After all, virally-infected cells don’t normally traffic to 2˚ lymphoid organs

“Classic” view of CTL response

against virus-infected cells

PVR expressed on



Endocytosis of

virus, nuclear entry,

synthesis of viral

proteins in cytosol.

Infection with


Presentation of

viral peptides on

MHC Class I to CD8+

cytotoxic T-cells

Proliferation of

cytotoxic T-cells



mediated cell death

Cross-priming of exogenous

antigens by dendritic cells


protein export;


proteolysis of viral proteins;

Presentation of peptide via

MHC Class I


mediated cell death

of DC; proliferation

of CD8+ CTL;

Killing of virus-infected

epithelial cells by CTL


changes; recognition

and phagocytosis

by dendritic cell

PVR expressed on



Infection with


Cross priming a dendritic cell engulfs a viral infected macrophages

Cross-priming: A Dendritic Cell Engulfs aViral-infected Macrophages

Influenza-infected MF

Dendritic Cell

From: Albert et al., J. Exp. Med. 188:1359, 1998

Cd8 t cells need help with their memory

CD8 T Cells Need Help With Their Memory

CD4 Help

1º effectors


2º effectors

No help

Cooperation in killing granzyme and perforin

Cooperation in Killing:Granzyme and Perforin




Barry & Bleackely. Nature Rev. Immunol. 2:401, 2002 Lieberman. Nature Rev. Immunol. 3:361, 2003

Cellular events at the synapse between ctl and target cells

Cellular Events at the Synapse Between CTL and Target Cells

Transfer of membrane proteins at the synapse. (a–e) A series of still frames from a movie showing CTLs killing a target cell, the membrane of which has been labeled with a fluorescent protein marker, and electron micrographs showing roughly equivalent stages of synapse formation. Granules polarize towards the immunological synapse as the CTL engages its target (a–c); as the CTL disengages, the granules withdraw from the synapse (d), where membrane from the target has accumulated. As the CTL detaches, target membrane is ripped off the dying target (e), and the CTL can engage a new target (color panel of e).

Trambas & Griffiths. Nature Immunol. 4:399, 2003

Human diseases involving defective granule killing

Human Diseases Involving Defective Granule Killing

Disease Gene Clinical Manifestations

Chediak-Higashi CHS1 Syndrome

Griscelli Syndrome Rab27a

Hermansky-Pudlak HPS1


Familial Hemophagocytic Perforin

Lymphohistiocytosis (30% of cases)

Lysosomal inclusions in all leukocytes

Recurrent bacterial infections

Decreased NK cell function

Oculocutaneous albinism (melanosome defect)

Bleeding (platelet storage granule defect)

Partial albinism

Hepatosplenomegaly (lymphohistiocytic infiltration)

Decreased NK cell function

Oculocutaneous albinism (melanosome defect)

Bleeding (Platelet storage granule defect)

Pulmonary fibrosis (Type II cell surfactant

body inclusions)

Hepatosplenomegaly (accumulation of

activated T-cell and macrophages)

Decreased NK cell function


Life and death in the fas lane

Life (and Death) in the Fas Lane

Barry & Bleackely. Nature Rev. Immunol. 2; 401-409 (2002)

Viral evasion of immunity

Viral Evasion of Immunity

Barry & Bleackely. Nature Rev. Immunol. 2; 401-409 (2002)

Cross priming dcs fight back

Cross-priming: DCs Fight Back

Infected DC Infected tissue cell Cross-presenting DC

B cells T cells

Innate-like Lymphocytes


NK, NKT, gd

Time Course of Innate and Adaptive Immunity

Time Course of thePrimary Immune Response

Innate immunity

Acquired immunity

Distinctions Between Innate and Adaptive Immunity

Innate immune system Adaptive immune system

Receptors Germline-encoded Somatically engineered

Distribution Non-clonal Clonal

Kinetics Rapid Slow

(requires clonal expansion)

Specificity Recognizes non-self Recognizes “altered self”

“pattern recognition” Primary structure (TCR)

Higher order structure

(Immunoglobulin; BCR)

Effector Cells All Primarily lymphocytes,

DCs, Mf

Innate-like B Lymphocytes

NK cells

not MHC


Thymus-independent Antigens are

Presented to Specialized B-cells

Marginal zone B cells, like B-1 cells, respond to carbohydrate

antigen and secrete mainly IgM

Like students who cram, after the initial encounter of Ag,

they demonstrate little memory







Innate-like T Lymphocytes:

NK Cells

NK cells

not MHC


Immunology course general principles

Natural Killer Cell

Immunology Course-General Principles

Gene structure of the human mhc

Major Genes in the MHC Class I Region

Gene Structure of the Human MHC

The human MHC covers ~4 Mbp of DNA on chromosome 6p21.3 and contains over 220 identified loci. It has been divided into three regions: class II (centromeric), class III, and class I (telomeric) with extended class I and class II regions on either side. This is one of the most gene-dense regions of the human genome. It encodes the most polymorphic human proteins known to date. Of the expressed loci in the MHC, roughly 40% are associated with the immune system. They include the classical class I, HLA-A, -B, and -C, nonclassical HLA-E, -F, and -G, as well as ''postmodern'' MICA and MICB genes (MHC class I chain-related genes). The products of classical polymorphic class I genes, HLA-A, B, and C, interact with T cell receptor (TCR) molecules as well as with the products of the killer immunoglobulin-like receptor (KIR) genes expressed on natural killer cells and some T cells.

Trowsdale., Immunity. 15:363, 2001

One Mechanism of Triggering

NK Cell Cytotoxicity

The NKG2D-DAP10 receptor complex and its ligands. A representation of NKG2D-DAP10 receptor expression and the interaction of NKG2D-DAP10 with its ligands. Cytotoxicity requires the expression of ligands of NKG2D (e.g., MICA, MICB) in the target cells.

Lanier, Nature Immunol. 2:23, 2001

Why do NK Cells Fail to

Recognize Healthy Cells?

The Balance of Activating and Inhibitory Signals

Determines the Outcome of the NK Effector Response
























PI 3-kinase




Syk: a protein tyrosine kinase

PI 3-kinase: a phosphoinositide kinase

SHP-2: A protein tyrosine phosphatase


Cytokine Secretion

X linked lymphoproliferative disease

X-linked Lymphoproliferative Disease

Rare (prevalence of 1/1,000,000)


Defect in cytotoxicity

Uncontrolled T-cell activation from excessive cytokine

secretion, especially in response to EBV infection

Defect apparent in NK cells and CTL

Patients are treated with bone marrow transplantations

of hematopoietic stem cells

Innate-like T Lymphocytes

NK cells

not MHC


The nkt cell recognizes glycolipid antigen presented by cd1 on the apc

The NKT Cell Recognizes Glycolipid AntigenPresented by CD1 on the APC

DCs that are infected with intracellular bacteria present foreign bacterial lipid antigens on the cell surfac

bound to CD1 molecules. CD1-restricted T cells that are specific for the foreign microbial lipids are stimulated

to carry out effector functions, including the secretion of cytolytic granules containing perforin and granulysin,

which lyse the infected cells and have direct antimicrobial effects, respectively, and the production of

IFN-g and TNF-a, which activate the microbicidal functions of macrophages.

Where Do NKT Cells Fit In?



High IL-4 production

Rapid cytokine


Non-MHC restricted







MHC-restricted Thymus-independent




1. For cytotoxic CD8 T-cells, ligation of the TCR by MHC I/peptide + co-stimulation

results in release of granzymes and perforin and/or FasL, leading to apoptosis

of the target cells.

2. Viruses evade host defense, in part, by down-regulating MHC Class I. Uninfected

dendritic cells circumvent this by “cross-priming”: phagocytosis of virus-infected

cell and presentation of “exogenous” viral antigens on MHC Class I.

3. The innate immune system has a rapid onset and recognizes molecular patterns

in a non-clonal fashion.

4. NK cells lack TCRs, but instead express both activating and inhibitory (e.g., KIRs)

receptors at their surfaces. The relative expression and ligation of these receptors

determines the outcome (i.e., killing or not) of the NK effector response.

5. Innate immune B-cells (e.g., B-1 cells and marginal zone B cells) recognize

carbohydrate antigens, secrete IgM, and are not long-lived.

6. Innate immune T-cells (gd T-cells, and NK T cells) recognize non-peptide antigens in

non-classical MHC-like molecules. They mediate cytotoxicity & rapid cytokine secretion.