Biotechnology and Pharmacology Course Topic 07

CELL-MEDIATED IMMUNITY
A/Prof. Le Van Dong MD., PhD
Former Deputy Head, Department of Immunology
Vietnam Military Medical University
Tel: 0989058710; Email: levandong@vmmu.edu.vn

EDUCATION
RESEARCH
INDUSTRY/ TREATMENT

Immunology Journey
Topic 1: Introduction to Immunity and Immune Systems
Topic 2: Cells and Organs of the Immune System
Topic 3: Innate Immunity
Topic 4: Antigens
Topic 5: Antibodies
Topic 6: Humoral Immune Response

Topic 7: Cell-Mediated Immunity

Topic 8: Immune Responses Against Tumors and Transplants
Topic 9: Hypersensitivity Diseases, Immunodeficiencies and Autoimmunity
Topic 10: Immunotherapy
Topic 11: Common immunological techniques

Contents
1. Experiments leading to the
understanding of immunity to
tuberculosis and cell-mediated
immunity (CMI).
2. Mechanisms of CMI.
3. Roles of CMI in defense against
intracellular pathogens, cancer and
transplantation.

Types of immunity
Abbas A. K and Lichtman A. H
Basic Immunology 3rd Ed Saunders 2011

Adaptive immune response which:

Produces specific Abs called Humoral Immune Response
Produces specific T cells called Cell-mediated Immune Response

Immune response to M.tuberculosis

Robert Kochs experiment

Inject Mycobacterium tuberculosis (Bacille de

Koch: BK) to a BK nave animal. After few days
the injected site got swollen, necroses; massive
necrosis, systemic tuberculosis happened and
the animal died.

Inject BK to animal survived after BK challenged.

After few days the injected site got swollen,
necroses; limited necrosis, no systemic
tuberculosis happen, the animal survived.

Kochs experiment
Systemic
tuberculosis;
died

BK

BK nave mouse

No systemic
tuberculosis;
survived

Mouse survived
after BK challenged

Experiment of Landsteiner&Chase

Transfuse serum from mouse survived after BK

challenged to a BK nave mouse (passive
immunity). Challenge with BK, the animal
develops systemic tuberculosis and dies.

Inject white blood cells (most are lymphocytes)

from mouse survived after BK challenged to a BK
nave mouse (adoptive immunity). Challenge with
BK, the animal does not develop systemic
tuberculosis and survives.

Landsteiner-Chases experiment
Antibody
Passive
Immunity

Systemic
tuberculosis;
died

BK

Mouse
survived after
BK challenged

Lymphocytes

Adoptive
Immunity

No systemic
tuberculosis;
survived

Luries experiment

Take Macrophage (M) from BK nave rabbit, mix with

BK to allow M eat BK. Inject BK loaded M to ocular
cavity of BK nave rabbit. The animal DEVELOPS
systemic tuberculosis and dies. Note: M from BK nave
animal can eat BK but can not kill BK.

In contrast, take M from rabbit survived after BK

challenged, mix with BK to allow M eat BK. Inject BK
loaded M to ocular cavity of BK nave rabbit. The
animal DOES NOT develop systemic tuberculosis and
survives. Note: M from BK primed animal can eat BK
and can also kill BK.

Luries experiment
M

M phagocytosed BK

BK nave
rabbit
BK

Excess BK

Systemic
tuberculosis;
died

M phagocytosed BK

M
Rabbit survived
after BK
challenge

No systemic
tuberculosis;
survived

Notes
BK infected animal produces both specific
antibody to BK but that antibody can not protect the
animal from tuberculosis. Only specific lymphocytes
can protect the animal from tuberculosis.
BK is inside the cell while antibody is in blood.
There must have other mechanism to kill BK to
protect the animal from tuberculosis.
It was then turned out that the lymphocytes are T
lymphocytes and that mechanism being called cellmediated immunity (CMI).

Two types of CMI

Type 1: mediated by TCD4+; TCD4+

acts on functions of macrophage to
eat then kill microbe (delayed-type
hypersensitivity).

Type 2: mediated by TCD8+; TCD8+

kills targeted cell (direct cytotoxicity).

Type 1: Delayed-type

Type 2: Direct cytotoxicity

Abbas A. K and Lichtman A. H Basic Immunology 2nd Ed Saunders 2004

Type 1: mediated by TCD4+; TCD4+

activates macrophage to kill microbe

TCD4+ can recognize antigenic determinant of

extracellular antigens processed and presented by APC
such as macrophage.

TCD4+ uses TCR to recognize antigenic determinant;

CD4 molecule is co-receptor to recognize MHC class II
molecule which presenting the antigenic determinant.

Both TCR and CD4 molecules need to recognize their

ligands at the same times. This is being called doublerecognition.

Double-recognition is mechanism to regulate the immune

response to the real pathogen.

Extracellular antigen process

Cell membrane
Capture

Antigen protein
in endosome
Endosome

pH

To lysosome

Enzyme protease digest protein as pH decreases

Loading peptide antigen on MHC class II

Cell membrane
Capture

MHC in ER

Endosome

Antigen peptide-MHC class II

presented on cell surface
Cell surface (t1/2 = 50hr)

To lysosome for degradation

Antigen presentation to TCD4+

TCD4+

TCR

MHC class II
CD4

Macrophage

Activation of macrophage and its

response after got activated

Abbas A. K and Lichtman A. H Basic Immunology 2nd Ed Saunders 2004

Notes

Macrophage needs to produce more enzyme

from lysosome to kill microbe, these enzymes
can also cause injury to nearby tissues. This
injury happened strongly and suddenly so is
called hypersensitivity.

Activation of TCD4+ and mobilization of

macrophage take 48-72 hours, so such
hypersensitivity being called delayed-type
hypersensitivity (DTH).

The TH1 population take part in this activity is

called
TDTH
(coming
from
delayed-type
hypersensitivity).

Type 2: mediated by TCD8+; TCD8+ kills

targeted cell

TCD8+ can recognize antigenic determinants of

intracellular antigen which is processed and presented by
virus infected cells or cancer cells.

TCD8+ uses TCR to recognize antigenic determinant;

CD8 molecule is co-receptor to recognize MHC class I
molecule which presenting the antigenic determinant.

Both TCR and CD8 molecules need to recognize their

ligands at the same times. This is being called doublerecognition.

Double-recognition is mechanism to regulate the immune

response to the real pathogen.

Endogenous antigen process

(virus antigen, cancer antigen)
Degradation in proteasome

ER
Newly formed MHC class I

Cytoplasm

Antigen peptide load on MHC class I

ER

Peptide

Peptide

Cell surface

To lysosome for degradation

Ag presentation to TCD8+
TCD8+

TCR

MHC class I
3

CD8

VIRUS INFECTED CELL

OR CANCER CELL

Activation of TCD8 to become

cytotoxic T lymphocyte (CTL)

Basic Immunology 2nd Ed Saunders 2004

Basic Immunology 2nd Ed Saunders 2004

Janeway et al. Immunobiology 6th Ed Garland Science 2005

Role of CMI response

CMI has important roles in:
Defense against intracellular pathogen
Immunity to cancer
Graft rejection

Targets of CMI

Type 1

Abbas A. K and Lichtman A. H Basic Immunology 2nd Ed Saunders 2004

Co-ordination between two types of CMI to fight

to intracellular microbes

Abbas A. K and Lichtman A. H Basic Immunology 2nd Ed Saunders 2004

CMI against cancer

CTL kill cancer cell

CTL

Perforin
Granzyme B

FasL
TCR

Fas (CD95)
MHC class I + Ag

CANCER CELL

Apoptosis

Graft rejection: both types

Kuby Immunology 5th Ed Freeman and Company 2003

Evaluation of CMI
Tuberculin test

Tuberculin test

Tuberculin test is used to check if a person has developed

CMI to M. tuberculosis.
Positive results is good, negative results is not good.
The test is not for diagnosis of tuberculosis disease.

Abbas A. K and Lichtman A. H Basic Immunology 2nd Ed Saunders 2004

Review questions
1. Describe experiments done by Koch, Landsteiner
Chase and Lurie about immunity to tuberculosis
leading to the identification of a new immune
response mechanism.
2. Two types of CMI and their roles in defence against
intracellular microbes.
3. Principle and significance of tuberculin test.