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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 recognizeforeign 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 theimmune 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 andHumoral Immunity

Antibody ProductionT-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, andhapten-carrier molecules.

T-Independent Antigens:

• Antibody production does not require assistance from T cells.

• Antigens are mainly polysaccharides or lipopolysaccharides with repeatingsubunits (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, LeprosyListeriosis, Brucellosis,

Fungi – Histoplasmosis, Cocccidiomysosis,Blastomycosis,

Parasites – Trypanosomiasis

In transplantation immunity,Immunologioly in Transplantation, malignancy,

Pathogenesis of Autoimmune diseases

7DR.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 typeadjuvant.

9DR.T.V.RAO MD



FUNCTIONS OF T CELLS

• Cytotoxic T cells

recognize antigen on

surface of virus

infected cells, tumorcells, allograft cells

with MHC I and

sectored Lymhokinesand 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


DR.T.V.RAO MD 11




• 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 ofmacrophages or other cells complexes with MHC II

molecule – leads to release of BiologicalMediators Lymhokines – activate Macrophagesand kills intracellular parasites

12DR.T.V.RAO MD



T Cells and Cell Mediated ImmunityCellular 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 cellularcommunication

14DR.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 ofsecretion, or target of action. Because

cytokines are characterised by considerable

redundancy and pleiotropic, suchdistinctions, allowing for exceptions, are

obsolete.

17DR.T.V.RAO MD



DEFINITIONS

• Lymhokines Biologically active substance released by

activated T Lymphocytes

•

Monokines – Substances secreted by Monocytes andMacrophages

• Interleukins – Produces by lymphocytes which exert a

regulatory effect on other cells

• All above grouped under cytokines

18DR.T.V.RAO MD



DEFINITIONS

• Autocrine, if the cytokine acts on the cell thatsecretes 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 toantibodies have a stronger immune effect than thecytokine alone. This may lead to lower therapeuticdoses.

19DR.T.V.RAO MD



• They are peptidemediators, intracellularmessengers, whichregulate immunological,

inflammatory andreparative host cellresponses

• They are potent hormones Active even at Fetomolar

concentrations produced bywidely 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 H VE

• Paracrine effect – acts

locally – near the

producing cells

• Having pleotrophic

effects – Multiple

effects on growth and

differentiation ofvarious cell types.

DR.T.V.RAO MD 22



IMPORT NT 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

23DR.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 hoursDR.T.V.RAO MD 24



FUNCTIONS OF INTERLEUKIN 1

DR.T.V.RAO MD 25

• IL1 stimulates T cells and Produces IL2 and otherLymhokines

• Helps B cell proliferation

• Synthesizes Antibodies

• Helps Neutrophils in Chemo taxis

• Promotes Phagocytosis

• Promotes Metabolic Physiological and inflammatoryresponses by action on Bone marrow



IL1 INITIATES FEVER

• IL1 is crucial inpromoting fever andcalled as Pyrogens.

• With the help of TumorNecrosis factor causeshematological changes

in Septicemias, Shockand bacterialmeningitis

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.27DR.T.V.RAO MD



OTHER INTERLEUKINS

• Interleukin 4 Acts as a Growth factor for TLymphocytes

• Interleukin 5 Causes the proliferation of

activated B Lymphocytes

• Interleukin 6 Produced by Stimulated B and TLymphocytes Induces the production of

Immunoglobulin synthesis Stimulates theHepatocytes, nerve cells,Hematopoetic cells

28DR.T.V.RAO MD



INHIBITORY CYTOKINES

• Some cytokines arepredominantlyinhibitory. For

example, IL-10 andIL-13 inhibitinflammatory

cytokine productionby 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





• Primarily identified asAntiviral agents

• Now classified as Cytokines

• Interferons play an important

role in the first line of defenceagainst viral infections. Theyare part of the non-specificimmune system and areinduced at an early stage in

viral infection – before thespecific immune system hashad 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; theythen bind to receptors on

target cells and induce

transcription

of approximately 20-30genes 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 producedby 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 theyenhance the immune system’s ability

to recognize foreign invaders,

enabling the system as a whole tofunction more effectively

35DR.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-infectedepithelial cells.

• Interferon-gamma (immune interferon) isproduced by certain activated T-cells and NK cells.

• Interferon-gamma is made in response to antigen(including viral antigens) or mitogen stimulation oflymphocytes.

36DR.T.V.RAO MD



• Interferon-Gamma is

involved in the regulation of

immune response

throughout the body.

Interferon-Gamma is thesignalling protein that gets

the immune system as a

whole ready for attack and

fine tunes it to quickly andeffectively get rid of foreign

and unwanted intruders

INTERFERON GAMA

DR.T.V.RAO MD 37



• Interferon-gamma has beenused to treat a variety ofdisease in which macrophageactivation might play animportant role in recovery, eg.

lepromatous leprosy,leishmaniasis, toxoplasmosis.Since interferons have anti-proliferative effects, they havealso been used to treat certain

tumours such as melanomaand 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 theory4 Clonal selection theory

39DR.T.V.RAO MD



JERNE’S NETWORK HYPOTHESIS

• It explains the mechanism of antibody response

• The variable region of an immunoglobulin moleculecarrying 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 termedas idiotype

• Produce antiidotypic antibodies

• Which in turn produce antibodies to them

40DR.T.V.RAO MD



• Burnet proposedthe theory 1957

• The theory emphasizes theimmunological specificity to

cellular level

In this theory the cell are formedby somatic mutation, the cellsthat react with self antigens areeliminated and called as

Forbidden clones.

Their persistence in laterlife leads to Autoimmuneprocess

WHAT IS CLONAL SELECTION THEORY

DR.T.V.RAO MD 41



NOBEL PRIZE WINNING THEORY

• Which in turn produceantibodies to them

• Forms a idiotype network

• The above processcontrols the amount ofantibodies

• The above theory byNiels K.Jerne wasawarded Nobel Prize forMedicine 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 forseparate regions of the

antibody molecule

RECENT THEORIES

DR.T.V.RAO MD 44



• Programme created by Dr.T.V.Rao MD

for Medical and Paramedical Students in

the Developing World

• Email

•

[email protected]

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