Transcript Cytotoxic T cells

Introduction To Immunology
Dr.Firas Al-Tae
PhD Immunology, University of Liverpool,UK
• Immunology: Deals with the body protective
and defence mechanisms against diseases:
Infections,
Tumours
Clearance of dead cells and tissue repair
Vaccination
Allergy and Hypersensitivity
Tranplant rejection etc..
• Immunity:
Original meaning
"Exemption from government taxes"
In the context of immunology
"Collective defense mechanisms against diseases"
• The cells and molecules responsible for the immunity are
called immune system
Immunity:
• The efforts of the immune system in regards to any
etiological agent are called immune responses
• Usually against foreign immunogens, useful
• Sometimes harmful, against self immunogens!!!!!!
Autoimmunity and graft rejection
Types of Immunity
Innate (non-specific)
immunity
Adaptive (specific) immunity
- Present from birth;
- Not present at birth but aquired
- Our First Line Of Defenses;
- Rapid starts within min-hours
after encoutering pathogens;
- Non specific, prevents almost
ALL pathogens from causing
diseases;
during life as immune system
developes;
- Late , starts days after first
infection;
- Specific, reacts specifically with
specific immunological molecules
(antigens)
Types of Immunity- continue
Innate (non-specific)
immunity
Aquired (specific) immunity
- No memory cells;
- Memory cells
“Memory” in adaptive immunity
1st infection
memory
Slow response
Pathogen proliferate
2nd infection
Fast response
Pathgen
killed
Disease
No disease
Symptoms
No symptom
Antigens (Ags)
• Foreign substance ---- Antigen
• If able to produce immune response ------immunogen or complete antigen
• If unable to initiate immune response alone called
partial antigen
• All immunogens are antigenic but not all antigens
are immunogenic
• Immune system does not react against the whole
pathogen but part of it (Ags) and not against the
whole Ag but parts of it (chemical groups) called
epitopes
• Each Ag has variable number of epitopes
Properties of Antigens
1. Foreignness
• A) Autologous antigens : Self antigens and there
will be no immune response.
• B) Allogenic antigens : from the same species
and there may be reaction, eg. Blood transfusion,
kidney transplant
• C) Heterologous antigens: from different
species.These antigens will be rejected and there
will be severe immune response
Properties of Antigens
2. Chemical complexity
Most antigens contain at least one amino acid in their
structures. More amino acid more antigenesity
3. Molecular weight
More than 100,000 more immunogenic
Elements of Innate and
Adaptive Immunity
Elements of Innate Imuunity
1. Epithelial Barriers (Skin , Mucosal Tissues ,
GIT flora and Lysozymes)
- Act as physical or chemical barriers
- Structural integrity of skin and muous membranes prevent COLONIZATION
- Damaged surfaces—abraded skin are often readily colonized promoti
invasion of this and other tissue
Chemical and Physical BarriersThe Skin Microorganisms normally
Associated with skin prevent
Potential pathogens from
Colonizing
Sebaceous glands secrete
Fatty acids and lactic acid
Which lower the skin pH
(pH 4-6)
Unbroken skin is a contiguous
Barrier
The skin has a low moisture
content
Chemical and Physical
Barriers-Mucosal membranes
Ciliated epithelial cells lining the trachea remove microbes inhaled
through the nose and mouth.
Mucus secreted by these cells prevent the microbes from associating
Too closely with the cells
Cilia push microbes upwards until they are caught in oral secretions
and expectorated or swallowed.
Chemical and Physical BarriersNormal Flora of the Gastrointestinal
Tract
Chemical and Physical BarriersLysozyme of the eye and kidney
Lysozyme constantly baths the kidney and the surface of the eye (tears).
(also in the female urogenital tract, and saliva)
Lysozyme breaks the glycosidic bonds between the NAG and NAM
that make up the backbone of peptidoglycan—causing bacteria to lyse.
Chemical and Physical
Barriers-Extracellular fluids
Blood plasma contains bacteriocidal substances
Blood proteins called beta-lysins bind to and disrupt the bacterial
cytoplasmic membrane—leads to leakage of the cytoplasmic constituents
and bacterial cell death
Elements of Innate Immunity
2. Phagocytes
- Cells that engulf, digest and destroy pathogens
- Include :
- Neutrophils
- Monocytes/Macrophages
- Natural Killer (NK) cells
Elements of Innate Immunity
Neutrophils
• Multi-lobular nucleus (PMNL)
• Highly mobile phagocytes
• Acute inflammation
• Containing bacteria-killing enzymes
Elements of Innate Immunity
Monocytes/Macrophages
- Blood
- Smaller
- Tissues
- 5-10 times larger
- More phagocytic activity
- Named Based on Tissue They Reside
Alveolar (lungs), Kupffer (liver),
Microglial (brain), Osteoclasts (bone)
Elements of Innate Immunity
Natural Killer (NK) cells (CD56+)
- Large round granular lymphocytes
- Always remain in the circulation
- Act as immunological surveyors (cytotoxic cells):
Kill virally infected cells
Kill tumours
• However, NK cells do not require stimulation, nor do they
exhibit memory cells. NK cells respond in the absence of
MHC proteins.
• What does CD refer to???????
CD (Cluster of Differentiation)
• CD = Cluster of differentiation
• Leukocytes surface antigens that are expressed on cells of
a particular lineage (“differentiation”)
• Also called CD molecules , CD antigens , CD markers
• Used to classify leukocytes into functionally distinct
subpopulations, e.g
• NK cells are CD56+
• T - Lymphocytes CD3+ ( pan T cells marker)
• B - lympocytes CD19+
• Monocytes / Macrophages CD14+
The Specific Immune Response
- Non-specific (innate) immunity IS
SOMETIMES NOT ENOUGH!!!
- Another more poweful type of immunity
called Specific (adaptive) Immunity is
required —That ACQUIRED ability to
recognize and destroy an individual pathogen
and its products
- Specific Immunity results from the actions of B and T lymphocytes pre
in the blood and lymph ( key players)
-Lymph is distinguished from blood in that it does NOT contain red blood
0.1% of the cells found in blood are the nucleated leukocytes (WBCs)
Lymph is composed entirely of leukocytes.
All immune cells including B and T lymphocytes are bone marrow-derive
distributed through out the body
Stem cells are the precursors to all of these cells
Origin and Development of B and T
Lymphocytes
• Origin : Stem cells in the bone marrow
1 ry
• Maturation : Bone marrow ( B cell maturtion)
lympoid
Thymus ( T cell maturation) organs
- From 1ry lympoid organs distributed throught lymph
and blood to 2ry lympoid organs:
Lymph nodes
Tonsils
Spleen
Mucosal tissues in lung and gut
Types of specific
(adaptive) immunity
Humoral
immunity
Cellular immunity
Overview of the specific (adaptive)
immune response
1. Cell Mediated Immunity ( T cell mediated immunty)
Key players : T lymphocytes. Two types:
Cytotoxic T cells (CTL) or (CD8+)
T helpers ( TH) cells (CD4+)
- Cytotoxic T cell directly attack and destroy antigen-bearing cells
especialy virally infected cells and tumours
- Helper T cells act indirectly by secreting proteins called cytokines that
activate other cells such as macrophages to destroy the antigen-bearing cells
CAN you name another immunological cell type that also functions as
CYTOTOXIC cells ?????.What are the main differences between them?
Mechanism of cytotoxicity by CTL
(CD8+)
• T lymphocytes can not recognize and
respond to free antigens
T
lympho
cytes
+
=
Free
antigens
No
action
Mechanism of cytotoxicity by CTL
(CD8+)
• 1st step : virally infected or tumour transformed
cells will be engulfed by the phagocytes
(macrophages) at the site of infection or
transformation (internalization)
• Next , internalized antigen is processed
inside the macrophages where the antigen is
degraded and fragment of it binds to MHC
class I molecule
Major Histocompatibility complex proteins are
found on the surface of cells:: T cells cannot recognize
foreign antigens unless they are associated with these MHC proteins
Class I MHC proteins are
found on the surface of ALL
nucleated cells
Class II MHC proteins are only
found on the surface of
B lymphocytes, macrophages
and other antigen presenting cells
ALL MHC proteins are imbedded in the cytoplasmic membrane of
cells and project outward from the cell surface
Mechanism of cytotoxicity by CTL
(CD8+)
• THEN , the processed antigens bind to Class I
(Ag-MHC class I complex ) are transported to
the
cell surface
- The phagocytes ( macrophages) now move
toward regional lymph nodes under the
influence of certain chemical substances
(chemotaxis)
Mechanism of cytotoxicity by CTL
(CD8+)
• In the regional lymph nodes the phagocytes
present the antigen in association with
MHC class I molecule to lymphocytes.
• That is why phagocytes ( macrophages) are
called antigen presenting cells (APC).
Mechanism of cytotoxicity by CTL
(CD8+)
• CTL interact SPECIFICALLY with the antigen MHC class I complex through TCR (T Cell
Receptor).
• Each T cell has thousands of copies of the SAME
TCR on its surface
• The immune system can generate TCRs that will
bind nearly every known peptide antigen
Structure of the T-cell
receptor (TCR). The V
domains of the alpha chain
and beta chain combine to
form the peptide antigenbinding site.
The T cell receptor extends
from the surface of a T cell
Cytoplasmic membrane of
a T cell
Class I MHC proteins and
cytotoxic T cells (Tc)
Class I pathway is useful in destroying
cells that have been infected by viruses or
have been transformed by tumors
1. Protein antigens manufactured in the cell
by viruses or tumors are degraded in the
cytoplasm and transported to the
endoplasmic reticulum
2. The processed antigens bind to Class I
MHCs and are transported to the cell
surface
3. Together this complex interacts with the
TCR of a Tc cell, the binding of the
complex with the TCR is strengthened
buy a CD8 coreceptor
Class I MHC proteins and cytotoxic T cells
(Tc)
The cell-cell interaction between
the infected cell and the Tc
cell is mediated by the
MHC class I - antigen complex and
TCR
The Tc cell produces cytotoxic proteins
perforins—produce holes or pores in the
target cell and granzymes enter the
virus infected cell causing apoptosis or
programmed cell death
The cytotoxic proteins only affect those
cells to which the Tc cell has specifically
interacted
Mechanism of cytotoxicity by CTL
(CD8+)
• The first contact of the CTL with the antigen is
called primary immune response. This will take
time to develope (usually several days) and
associated with development of memory cells.
• When the CTL come in contact with same antigen
for second time , this is called secondary immune
response.Usually faster than 1ry immune reponse
and more stronger that leads to eradication of
pathogen before symptoms appear.