الرحمن اللة الرحمن بسم اللة بسمالرحيمالرحيم

Cell Mediated Cell Mediated ImmunityImmunity

Cell Mediated ImmunityCell Mediated Immunity* Host defenses against extracellular infection * Host defenses against extracellular infection

areare mediated by:mediated by: - Antibody - Antibody - Complement- Complement - Macrophages- Macrophages

* Intercellular infections are mediates by CMI* Intercellular infections are mediates by CMI

* CMI are responsible for:* CMI are responsible for: - Resistance to intracellular pathogens- Resistance to intracellular pathogens - Resistance to fungal and protozoal - Resistance to fungal and protozoal

infectionsinfections - Resistance to tumors - Resistance to tumors

Cell Mediated ImmunityCell Mediated Immunity* CMI may play a role in some harmful * CMI may play a role in some harmful

conditions:conditions: - Hypersensitivity reactions type - Hypersensitivity reactions type IV (contact IV (contact

dermatitis)dermatitis) - Graft rejection- Graft rejection - Autoimmune diseases- Autoimmune diseases

* Cell mediated cytotoxicity mediated by:* Cell mediated cytotoxicity mediated by: - T-cytotoxic cells cells- T-cytotoxic cells cells - Natural killer cells - Natural killer cells - Activated macrophages- Activated macrophages

Characters Of CMICharacters Of CMICellular immune response is Cellular immune response is

mediated by:mediated by:

- Subpopulation of T-lymphocytes- Subpopulation of T-lymphocytes

- Macrophages and their - Macrophages and their productsproducts

Characters Of CMICharacters Of CMI* Macrophages present antigen * Macrophages present antigen viavia their surface MHC to T-cells their surface MHC to T-cells

* T-cells * T-cells recognizerecognize antigen through their specific receptors antigen through their specific receptors (TCR)(TCR)

* A specific T-cell clone becomes * A specific T-cell clone becomes activatedactivated and begins to and begins to proliferate proliferate

* Activated TH lymphocytes becomes effectors cells that secrete * Activated TH lymphocytes becomes effectors cells that secrete cytokinescytokines

Characters Of CMICharacters Of CMICytokinesCytokines stimulate other effectors cells of CMI and humoral stimulate other effectors cells of CMI and humoral

immune response and mediate the following:immune response and mediate the following:

- - Attract Attract monocytes, macrophages and lymphocytes to the monocytes, macrophages and lymphocytes to the sitesite

- - ActivateActivate macrophages to kill intracellular microbes macrophages to kill intracellular microbes

- - Promote activity of Promote activity of CD8 CTLs which directly kill virus CD8 CTLs which directly kill virus infected cells, tumour cells, and graft rejectioninfected cells, tumour cells, and graft rejection

- They - They activateactivate NK cells increasing their cytotoxic functions NK cells increasing their cytotoxic functions

- - StimulateStimulate B-cells to differentiate into plasma cells that B-cells to differentiate into plasma cells that secret antibodiessecret antibodies

Phases Of CMIPhases Of CMI1) Antigen processing and presentation1) Antigen processing and presentation Protein antigens processed and converted Protein antigens processed and converted

to to peptides then bind to MHC molecules on peptides then bind to MHC molecules on

AAntigen ntigen PPresenting resenting CCell (APCs ) ell (APCs ) to be presented to T-cellsto be presented to T-cells

1) Antigen Processing and 1) Antigen Processing and PresentationPresentation

a- Extracellular proteins are internalized into a- Extracellular proteins are internalized into vesicular vesicular

compartment of APCs compartment of APCs (Dentritic, macrophages,B-(Dentritic, macrophages,B-cells)cells)

- They are degraded to generate peptides- They are degraded to generate peptides - These peptides bind into class II MHC molecules- These peptides bind into class II MHC molecules - Peptide-MHC II complex is transported to - Peptide-MHC II complex is transported to

surface surface of APCs to be presented to of APCs to be presented to CD4 THCD4 TH cells ( cells (T T

HHelper cell)elper cell) Outcome:Outcome: Secretion of cytokines by TH cellsSecretion of cytokines by TH cells

1) Antigen Processing and 1) Antigen Processing and PresentationPresentation

b- Endogenously synthesized proteins are degraded b- Endogenously synthesized proteins are degraded to peptidesto peptides (all nucleated cells e.g virus infected (all nucleated cells e.g virus infected cells)cells)

- They bind to class I MHC in endoplasmic - They bind to class I MHC in endoplasmic

reticulumreticulum - Peptide-MHC I complex is expressed on surface - Peptide-MHC I complex is expressed on surface

of nucleotide cells to be represented to CD8 of nucleotide cells to be represented to CD8 cytotoxic cellscytotoxic cells Outcome:Outcome: Killing of presenting cells by CTLsKilling of presenting cells by CTLs

2) Activation of T-cells2) Activation of T-cells* Mature CD4 and CD8 cells are activated by two signals:* Mature CD4 and CD8 cells are activated by two signals:

- - First signalFirst signal is recognition of antigenic peptide-MHC is recognition of antigenic peptide-MHC complex on surface of APC by TCR-CD3 complexcomplex on surface of APC by TCR-CD3 complex

- CD4 and CD8 molecules are co-receptors that - CD4 and CD8 molecules are co-receptors that stabilize the stabilize the

interaction of TH cells and TC-cells respectively with interaction of TH cells and TC-cells respectively with APCsAPCs

- CD3,CD4, and CD8 act as signal transduction - CD3,CD4, and CD8 act as signal transduction moleculesmolecules

- Second co-stimulatory signal- Second co-stimulatory signal is: is: interaction of CD28 on T-cells with CD7 on APCsinteraction of CD28 on T-cells with CD7 on APCs

2) Activation of T-cells2) Activation of T-cells* TH-cells * TH-cells expressexpress IL-2 receptors and IL-2 receptors and secretesecrete

cytokines including IL-2 cytokines including IL-2 * IL-2 * IL-2 auto activateauto activate TH-cells TH-cells* APC * APC releaserelease IL-I which IL-I which acts onacts on both APC and both APC and

TH cell to TH cell to promotepromote their activation their activation* All mentioned interactions lead to * All mentioned interactions lead to activationactivation of of

mature TH-cellsmature TH-cells* Mature TH-cells proliferate and differentiate * Mature TH-cells proliferate and differentiate

into into effectors antigen specific TH-cellseffectors antigen specific TH-cells releasing cytokinesreleasing cytokines

* Some of them become * Some of them become memory cellsmemory cells which which provide secondary immune responseprovide secondary immune response

* Cytokine released from activated TH-cells * Cytokine released from activated TH-cells activateactivate macrophages, NK and B-cells macrophages, NK and B-cells

Phases Of CMIPhases Of CMI* Activated CD8 TC-cells* Activated CD8 TC-cells proliferate and proliferate and

differentiate into a clone of differentiate into a clone of effectors effectors cells CTLscells CTLs

* Effectors CTLs* Effectors CTLs killkill target cells target cells i.e.i.e. nucleated cells (expressing MHC-I) nucleated cells (expressing MHC-I)

infected with infected with viruses, tumor cells or graft cellsviruses, tumor cells or graft cells

3) Activation of Macrophages and 3) Activation of Macrophages and Delayed Type Hypersensitivity Delayed Type Hypersensitivity

(DTH)(DTH)

* Activated TH cells (TH1) * Activated TH cells (TH1) secretesecrete IFN- IFN-γγ which which activates activates macrophages and increase their macrophages and increase their ability to ability to killkill ingested intracellular pathogens ingested intracellular pathogens

* The process of * The process of activationactivation of macrophages, NK of macrophages, NK cell and cytotoxic T-cells, infiltration and cell and cytotoxic T-cells, infiltration and proliferation of inflammatory cells, proliferation of inflammatory cells, stimulatedstimulated by cytokines released from TH-cells (TH1) is by cytokines released from TH-cells (TH1) is important protective mechanism against important protective mechanism against intracellular pathogenintracellular pathogen

3) Activation of Macrophages and 3) Activation of Macrophages and Delayed Type Hypersensitivity Delayed Type Hypersensitivity

(DTH)(DTH)

* * Activated macrophagesActivated macrophages can also can also killkill abnormal abnormal host cells (abnormal or tumor cells) host cells (abnormal or tumor cells)

* * Its ctotoxicityIts ctotoxicity is is non specificnon specific and and stimulatedstimulated by by TNF, nitric oxid, enzymes and oxygen TNF, nitric oxid, enzymes and oxygen metabolitesmetabolites

* * If infectionIf infection is is not fully resolvednot fully resolved, activated , activated macrophages cause macrophages cause tissue injury and fibrosistissue injury and fibrosis i.e. DTH reactioni.e. DTH reaction

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