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Cell mediated immunity
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Dr.T.V.Rao MD
CELL MEDIATED IMMUNITY
DR.T.V.RAO MD 1
Duality of Immune System
. Cell Mediated Immunity
• Involves specialized set of lymphocytes called T cells that recognize
foreign antigens on the surface of cells, organisms, or tissues:
• Helper T cells
• Cytotoxic T cells
• T cells regulate proliferation and activity of other cells of the
immune system: B cells, macrophages, neutrophils, etc.
• Defense against:
• Bacteria and viruses that are inside host cells and are inaccessible to
antibodies.
• Fungi, protozoa, and helminthes
• Cancer cells
• Transplanted tissue
DR.T.V.RAO MD 2
Relationship Between Cell-Mediated and Humoral Immunity
Antibody Production
T-Dependent Antigens:
• Antibody production requires assistance from T helper cells.
• A macrophage cells ingest antigen and presents it to TH cell.
• TH cell stimulates B cells specific for antigen to become plasma cells.
• Antigens are mainly proteins on viruses, bacteria, foreign red blood cells, and hapten-carrier molecules.
T-Independent Antigens:
• Antibody production does not require assistance from T cells.
• Antigens are mainly polysaccharides or lipopolysaccharides with repeating subunits (bacterial capsules).
• Weaker immune response than for T-dependent antigens.
CELL MEDIATED IMMUNE RESPONSES • Primary Function Of Cell Mediated Response
• Eliminate Intracellular Pathogens
• Eliminate Tumor Cells
• Both Ag Specific And Non-specific cells Are Involved
• Ag Specific: CD8+ Cells (TC) And TH (DTH)
• Non-specific: M, Neutrophils, NK
• Both Specific And Non-specific Require Cytokines
• Humoral And Cell Mediated Do Collaborate
• Ex. M Use Abs As Receptors To Recognize Target Cells
DR.T.V.RAO MD 4
CELL MEDIATED IMMUNITY
* CMI may play a role in some harmful conditions:
- Hypersensitivity reactions type IV (contact dermatitis) - Graft rejection
- Autoimmune diseases
* Cell mediated cytotoxicity mediated by:
- T-cytotoxic cells cells
- Natural killer cells
- Activated macrophages
DR.T.V.RAO MD 5
CELL MEDIATED IMMUNITY WORKS BY COMPLEX
MECHANISMS
LEAST UNDERSTOOD ???
DR.T.V.RAO MD 6
CMI HELPS IN • Delayed hypersensitivity • Immunity in infections caused by Obligate and facultative
intracellular parasites
• Eg – Tuberculosis, Leprosy
Listeriosis, Brucellosis,
Fungi – Histoplasmosis, Cocccidiomysosis,Blastomycosis,
Parasites – Trypanosomiasis
In transplantation immunity,
Immunologioly in Transplantation, malignancy,
Pathogenesis of Autoimmune diseases
7 DR.T.V.RAO MD
IMPORTANCE OF CELL MEDIATED IMMUNITY
• DiGeorge Syndrome Proves The Importance
• No Thymus, No T-cell Mediated Immunity
• Extracellular Infections Are Effectively Addressed
• Intracellular Infections Are NOT (viruses, intracellular bacteria)
• Cell Mediated Immunity Can Be Divided Into 2 Major Categories
• Effectors lyse target
• 2 groups of cells: CTLs (specific) and NK, M (non-specific)
• Effectors which are CD4+ and mediate DTH
DR.T.V.RAO MD 8
INDUCTION OF CELL MEDIATED
IMMUNITY • Depends on Nature of Antigenic stimulus
• Best developed after following infection with intracellular parasites
• Live vaccines highly stimulating
• Killed vaccine not very effective
• But effective if contains Freund type adjuvant.
9 DR.T.V.RAO MD
FUNCTIONS OF T CELLS
• Cytotoxic T cells
recognize antigen on
surface of virus
infected cells, tumor
cells, allograft cells
with MHC I and
sectored Lymhokines
and destroy target
cells
DR.T.V.RAO MD 10
• Only T cell dependent antigens
lead to development of CMI
• Certain chemicals which come in
contact with skin induces
Delayed hypersensitivity
• T Cell contain the specific
receptor ( TCR )
• One epitope ( Antigen ) on
contact with receptor undergoes
blast transformation
• Leads to Clonal proliferation
FUNCTIONS OF T CELLS
DR.T.V.RAO MD 11
FUNCTIONS OF T CELLS
• The stimulated cells undergoes blast transformation, Clonal proliferation
• Leads to Effectors cells and Memory cells
• T cell react on presentation with MHC
• Helper T cells when presented on surface of macrophages or other cells complexes with MHC II
molecule – leads to release of Biological Mediators Lymhokines – activate Macrophages and kills intracellular parasites
12 DR.T.V.RAO MD
T Cells and Cell Mediated Immunity Cellular Components of Immunity:
• T cells are key cellular component of immunity.
• T cells have an antigen receptor that recognizes and
reacts to a specific antigen (T cell receptor).
• T cell receptor only recognize antigens combined with
major histocompatibility (MHC) proteins on the surface of
cells.
• MHC Class I: Found on all cells.
• MHC Class II: Found on phagocytes.
• Clonal selection increases number of T cells.
DR.T.V.RAO MD 13
BROAD VIEW ON CYTOKINES
• Cytokines are a category of
signalling proteins and
glycoproteins that, like hormones
and neurotransmitters, are used
extensively in cellular
communication 14 DR.T.V.RAO MD
T CELLS ONLY RECOGNIZE ANTIGEN ASSOCIATED
WITH MHC MOLECULES ON CELL SURFACES
CENTRAL ROLE OF HELPER T CELLS
CYTOKINES • Cytokines have been classed as
Lymhokines, interleukins, and chemokine's,
based on their presumed function, cell of
secretion, or target of action. Because
cytokines are characterised by considerable
redundancy and pleiotropic, such
distinctions, allowing for exceptions, are
obsolete.
17 DR.T.V.RAO MD
DEFINITIONS
• Lymhokines Biologically active substance released by
activated T Lymphocytes
• Monokines – Substances secreted by Monocytes and
Macrophages
• Interleukins – Produces by lymphocytes which exert a
regulatory effect on other cells
• All above grouped under cytokines
18 DR.T.V.RAO MD
DEFINITIONS
• Autocrine, if the cytokine acts on the cell that secretes it.
• Paracrine, if the target is restricted to the immediate vicinity of a cytokine's secretion.
• Endocrine, if the cytokine diffuses to distant regions of the body (carried by blood or plasma).
• It seems to be a paradox that cytokines binding to antibodies have a stronger immune effect than the cytokine alone. This may lead to lower therapeutic doses.
19 DR.T.V.RAO MD
• They are peptide mediators, intracellular messengers, which regulate immunological, inflammatory and reparative host cell responses
• They are potent hormones Active even at Fetomolar concentrations produced by widely distributed cells
( Lymphocytes, Macrophages, Platelets, and Fibroblasts.
WHAT ARE CYTOKINES
DR.T.V.RAO MD 20
CYTOKINES WORK ON MULTIPLE
LINEAGES
DR.T.V.RAO MD 21
CYTOKINES HAVE
• Paracrine effect – acts
locally – near the
producing cells
• Having pleotrophic
effects – Multiple
effects on growth and
differentiation of
various cell types.
DR.T.V.RAO MD 22
IMPORTANT CYTOKINES
• Interleukin I 1979
• Interleukin I divided into Alpha and Beta
• IL1 is secreted by Macrophages, Monocytes other nucleated
cells.
• Stimulated by Antigens, Toxins, Injury, Inflammation,
• Inhibited by
• Cyclosporins,Corticosteiods,Prostaglandins
23 DR.T.V.RAO MD
HOW CTLS KILL • Phases In CTL Killing
• Conjugate formation
• LFA-1 (CTL) binds ICAMs (Target)
• LFA-1 changes to high avidity if Ag Is Recognized
• Activated LFA-1 persists for 5-10 mins
• Membrane attack
• Requires Ca2+ and energy
• Granules release Perforins (65 kDa) and Granzymes (serine proteases) at the junctional space
• Perforins polymerize forming cylindrical pores (5-20 nm), Ca2+ is needed
• Granzymes enter target cell
• Granzyme B can enter thru mannose-6-phosphate receptor in a vesicle
• DNA fragmentation
• CTL dissociation
• Target cell destruction
• Apoptotic death within a few hours
DR.T.V.RAO MD 24
FUNCTIONS OF INTERLEUKIN 1
DR.T.V.RAO MD 25
• IL1 stimulates T cells and Produces IL2 and other Lymhokines
• Helps B cell proliferation
• Synthesizes Antibodies
• Helps Neutrophils in Chemo taxis
• Promotes Phagocytosis
• Promotes Metabolic Physiological and inflammatory responses by action on Bone marrow
IL1 INITIATES FEVER
• IL1 is crucial in promoting fever and called as Pyrogens.
• With the help of Tumor Necrosis factor causes hematological changes in Septicemias, Shock and bacterial meningitis
DR.T.V.RAO MD 26
OTHER INTERLEUKINS
• Interleukins 2 Modulates the immune
response
• Major activator of T and B Lymphocytes
• Stimulates cytotoxic T cells and Natural Killer
cells.
• Interleukin 3 Stimulates multilineage
cells of the Hematopoietic system. 27 DR.T.V.RAO MD
OTHER INTERLEUKINS
• Interleukin 4 Acts as a Growth factor for T Lymphocytes
• Interleukin 5 Causes the proliferation of activated B Lymphocytes
• Interleukin 6 Produced by Stimulated B and T Lymphocytes Induces the production of Immunoglobulin synthesis Stimulates the Hepatocytes, nerve cells,Hematopoetic cells
28 DR.T.V.RAO MD
INHIBITORY CYTOKINES
• Some cytokines are predominantly inhibitory. For example, IL-10 and IL-13 inhibit inflammatory cytokine production by macrophages.
DR.T.V.RAO MD 29
• Cells Capable of Cytotoxicity Express Fc Receptors
• Antibody Binds Target Cell, Cytotoxic Cells Bind Fc Portion Of Ab
• Antibody Provides The Specificity
• Examples Of Cells Capable Of ADCC
• M, NK, Neutrophils, eosinophils
• Killing Of Target Is Accomplished
• Thru perforin, granzyme (NK, Eosinophils)
• TNF (M, NK)
• Lytic enzymes (M, Neutrophils, Eosinophils, NK)
ANTIBODY DEPENDENT CELL MEDIATED
CYTOTOXICITY (ADCC)
DR.T.V.RAO MD 30
DR.T.V.RAO MD 31
• Primarily identified as Antiviral agents
• Now classified as Cytokines
• Interferons play an important role in the first line of defence against viral infections. They are part of the non-specific immune system and are induced at an early stage in viral infection – before the specific immune system has had time to respond..
INTERFERONS
DR.T.V.RAO MD 32
• Interferons are made by
cells in response to an
appropriate stimulus, and
are released into the
surrounding medium; they
then bind to receptors on
target cells and induce
transcription
of approximately 20-30
genes in the target cells,
and this results in an anti-
viral state in the target
cells.
DYNAMICS OF INTERFERONS
DR.T.V.RAO MD 33
CLASSIFICATION OF INTERFERONS
• There are three
classes of
Interferons: Alpha,
Beta and Gamma.
Interferon Alpha and
Beta are produced
by many cell types
DR.T.V.RAO MD 34
FUNCTIONS OF INTERFERONS
• Interferons are within the cytokine
family of proteins. Interferons are
especially important because they
enhance the immune system’s ability
to recognize foreign invaders,
enabling the system as a whole to
function more effectively
35 DR.T.V.RAO MD
TYPES OF INTERFERONS • Interferon-alpha (leukocyte interferon) is produced
by virus-infected leukocytes, etc
• Interferon-beta (fibroblast interferon) is produced by virus-infected fibroblasts, or virus-infected epithelial cells.
• Interferon-gamma (immune interferon) is produced by certain activated T-cells and NK cells.
• Interferon-gamma is made in response to antigen (including viral antigens) or mitogen stimulation of lymphocytes.
36 DR.T.V.RAO MD
• Interferon-Gamma is
involved in the regulation of
immune response
throughout the body.
Interferon-Gamma is the
signalling protein that gets
the immune system as a
whole ready for attack and
fine tunes it to quickly and
effectively get rid of foreign
and unwanted intruders
INTERFERON GAMA
DR.T.V.RAO MD 37
• Interferon-gamma has been used to treat a variety of disease in which macrophage activation might play an important role in recovery, eg. lepromatous leprosy, leishmaniasis, toxoplasmosis. Since interferons have anti-proliferative effects, they have also been used to treat certain tumours such as melanoma and Kaposi’s sarcoma.
USES OF INTERFERONS
DR.T.V.RAO MD 38
THEORIES OF IMMUNE RESPONSE
• Several theories are considered
1 Direct template theory
2 Indirect template theory
3 Natural selection theory
4 Clonal selection theory
39 DR.T.V.RAO MD
JERNE’S NETWORK HYPOTHESIS
• It explains the mechanism of antibody response
• The variable region of an immunoglobulin molecule carrying the antigen combining site is different in different antibodies
• The distinct Aminoacid sequence at antigen combing site and the adjacent parts of the variable regions are termed as idiotype
• Produce antiidotypic antibodies
• Which in turn produce antibodies to them
40 DR.T.V.RAO MD
• Burnet proposed the theory 1957
• The theory emphasizes the immunological specificity to cellular level
In this theory the cell are formed by somatic mutation, the cells that react with self antigens are eliminated and called as Forbidden clones.
Their persistence in later life leads to Autoimmune process
WHAT IS CLONAL SELECTION THEORY
DR.T.V.RAO MD 41
NOBEL PRIZE WINNING THEORY
• Which in turn produce antibodies to them
• Forms a idiotype network
• The above process controls the amount of antibodies
• The above theory by Niels K.Jerne was awarded Nobel Prize for Medicine in 1984
DR.T.V.RAO MD 42
DR.T.V.RAO MD 43
• Now genetic basis of antibody
diversity is identified.
• The recent theory of Split
genes explains many
unknown mechanisms
• The theory says the
information occurs in
discontinuous stretches of
DNA, each coding for
separate regions of the
antibody molecule
RECENT THEORIES
DR.T.V.RAO MD 44
DR.T.V.RAO MD 45
• Programme created by Dr.T.V.Rao MD
for Medical and Paramedical Students in
the Developing World
