cmi lecture 17 2

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Maravillas ModernasCell Mediated Immunity (CMI)

– Lecture By – Dr. Deshkar D.W.

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Cell mediated immunity (CMI) is the specific immune response mediated by sensitized T – cells independent of Abs.

Cell Mediated Immunity

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Host defenses against extracellular infection are mediated by:

- Antibody - Complement - Macrophages

Intercellular infections are mediated by CMI

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CMI is the arm of Adaptive immune system, engaged in eradicating infections by intracellular organisms.

Cells of CMI – T Lymphocytes.

Cell Mediated Immune Reactions ---- TWO TYPES- CD4+ T cells – Activate macrophages to kill ingested

microbes that are able to survive within vesicles of phagocytes.

- CD8 +T cells (CTLs) – Kill cells harboring microbes in their cytoplasm , THUS eliminating reservoir of infection.


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

infections - Resistance to tumors


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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 - Natural killer cells - Activated macrophages


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Cellular immune response is mediated by:

- Subpopulation of T-lymphocytes

- Macrophages and their products

Caracteres of Cell Mediated Immunity

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Macrophages present antigen via their surface MHC to T-cells

T-cells recognize antigen through their specific receptors (TCR)

A specific T-cell clone becomes activated and begins to proliferate

Activated TH lymphocytes becomes effectors cells that secrete cytokines


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Cytokines stimulate other effectors cells of CMI and humoral immune response and mediate the following:

- Attract monocytes, macrophages and lymphocytes to the site

- Activate macrophages to kill intracellular microbes

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

- They activate NK cells increasing their cytotoxic functions

- Stimulate B-cells to differentiate into plasma cells that secret antibodies


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1) Antigen processing and presentation Protein antigens processed and converted to peptides then bind to MHC molecules on Antigen

Presenting Cell (APCs ) to be presented to T-cells

Phases of Cell Mediated Immunity

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1.Antigen Processing & Presentation

a- Extracellular proteins are internalized into vesicular compartment of APCs (Dentritic, macrophages-cells) - They are degraded to generate peptides - These peptides bind into class II MHC molecules - Peptide-MHC II complex is transported to surface of APCs to be presented to CD4 TH cells (T Helper cell) Outcome: Secretion of cytokines by TH cells

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1.Antigen Processing & Presentation

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

- They bind to class I MHC in endoplasmic reticulum - Peptide-MHC I complex is expressed on surface of nucleotide cells to be represented to CD8 cytotoxic cells Outcome: Killing of presenting cells by CTLs

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2.Activation of T cells

Mature CD4 and CD8 cells are activated by two signals:

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

- CD4 and CD8 molecules are co-receptors that stabilize the interaction of TH cells and TC-cells respectively with APCs - CD3,CD4, and CD8 act as signal transduction molecules

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

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2.Activation of T cells TH-cells express IL-2 receptors and secrete cytokines including IL-2

IL-2 auto activate TH-cells

APC release IL-I which acts on both APC and TH cell to promote their activation

All mentioned interactions lead to activation of mature TH-cells

Mature TH-cells proliferate and differentiate into effectors antigen specific TH-cells releasing cytokines

Some of them become memory cells which provide secondary immune response

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

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Phases of Cell Mediated Immunity

Activated CD8 TC-cells proliferate and differentiate into a clone of effectors cells CTLs

Effectors CTLs kill target cells i.e. nucleated cells (expressing MHC-I) infected with viruses, tumor cells or graft cells

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3.Activation of Macrophages & Delayed Type Hypersensitivity (DTH)

Activated TH cells (TH1) secrete IFN-γ which activates macrophages and increase their ability to kill ingested intracellular pathogens

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

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3.Activation of Macrophages & Delayed Type Hypersensitivity (DTH)

Activated macrophages can also kill abnormal host cells (abnormal or tumor cells)

Its cytotoxicity is non specific and stimulated by TNF, nitric oxide, enzymes and oxygen metabolites

If infection is not fully resolved, activated macrophages cause tissue injury and fibrosis i.e. DTH reaction

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Cytokines

Low molecular weight soluble proteins (polypeptides) produced in response to microbes and other antigens

They act via cell surface receptors to mediate and regulate the amplitude and duration of the immune-inflammatory responses, through activation of macrophages, controlling growth and differentiation of T and B cells

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General Properties Of Cytokines

* Cytokine secretion is a self limited event (transient)

* They are potent in minute amounts

* One cytokine can act on different cells (pleiotropic)

* Multiple cytokines may have the same functional effects (reduntant)

* Cytokines often influence synthesis and action of other cytokines

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* Two cytokines may antagonize each other’s action (produce additive or synergetic effects)

* Action of cytokine may be local or systemic

* Cytokine act close to the site of production (autocrine act.)

* Cytokine act on a nearby cell (paracrine action)

* Large amount secretion may enter circulation and act at a distance from site of production (endocrine action)

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* Their action is not antigen specific - It is initiated by binding to specific cytokine receptors on the membrane of target cells

* They act as intracellular messengers

* The response to cytokine is: a- Expression of new functions b- proliferation of target cells


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Functional Categories of Cytokines

Cytokines classified according to their biologic actions into three groups:

1) Mediators and regulators of innate immunity

- Produced by activated microphages and NK cells in response to microbial infection

- they act mainly on endothelial cells and leukocytes to stimulate the early inflammatory response to microbes

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Functional Categories of Cytokines

2) Mediators and regulators of acquired immunity - Produced mainly by T lymphocytes in response to specific recognition of foreign antigens - They include IL-2, IL-4, IL-5,, IL-13, IFN, Transforming growth factor-β (TGF-β) and lymph toxin (TNF- β)

3) Stimulators of haematopoiesis - Produced by bon marrow, stormal cells, leukocytes - Stimulate growth and differentiation of leukocytes - Stem cell factor, IL-3, IL-7, GM-CSF

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Interferons (IFNs)

* Interferons (IFNs): are proteins secreted in response to viral infections or other stimuli

* They include:

- INF-α produced by leucocytes induced by virus infected cells

- INF-β produced by fibroblasts

- INF-γ produced by NK cells,TH1 cells, CD8 T-cells

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Action of INF-α and IFN-β :

- Prevent viral replication - Increase MHC-I expression on viral infected cells helping their recognition by CD8 T-cells

- Increase cytotoxic action of Nk cells

- Inhibit cell proliferation and tumor growth

Interferons (IFNs)

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Action of IFN-γ : - Activate Macrophages - Increase expression of MHC-I and II on APCs - Enhance cytotoxic actions of Nk cells - Promote production of TH1 and inhibits proliferation of TH2

Interferons (IFNs)

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Therapeutic Uses of Cytokines 1) Interferon in treatment of viral diseases, cancer

2) Several cytokines are used to enhance T-cell activation in immunofideficincy diseases, e.g. IL-2, IFN-,TNF-

3) IL-2 and lymphokine activating killer cells (LAK) in treatment of cancer

4) GM-CSF induces increase in white cell count, it is used: a- To restore leukocytic count after cytotoxic chemotherapy induced neutropenia b- After bon marrow transplantation C- To correct AIDS-associated leukopenia

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5) Anti-cytokines antibodies in management of autoimmune diseases and transplant rejection: a- Anti-TNF in treatment rheumatoid arthritis b- Anti-IL2R to reduce graft rejection

6) Anti-TNF antibodies in treating septic shock

7) Anti-IL-2R in treating adult T-cell leukemia

8) Anti-IL-4 is under trial for treatment of allergies

Therapeutic Uses of Cytokines

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Detection of CMI Skin test – only method available till recently.

Now several in – vitro tests are available ------------

1. Lymphocyte transformation test - Transformation of cultured sensitized T – Lymphocytes on contact with specific Ag to blast cells - evidenced by enhanced DNA synthesis.

2. Target cell destruction - Killing of cultured cells by lymphocytes sensitized against them.

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3. Migration inhibition factor test – Most commonly used. Macrophages packed in a capillary tube are placed in a tissue culture medium in a chamber. Macrophages migrate out and spread over the glass walls of the chamber & form a lacy fan like appearance. If macrophages are from sensitized guinea pig, addition of Ag to the culture chamber inhibits the migration. This test – adopted for clinical use by incubating human peripheral leukocytes in capillary tubes to culture chambers. When a specific Ag is added , migration of leukocytes is prevented.

Detection of CMI

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cmi lecture 17 2

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