Cell Mediated Immunity(CMI)

Immune teamImmune team

Cell-Mediated Immunity (CMI)

Antigen T-lymphocytes

Immune responsesImmune responses

Cell Mediated Immunity

• Cell-mediated immunity (CMI).• Remember :-• CD4 ( T helper ) is attracted to MHC II • CD8 ( T cytotoxic ) is attracted to MHC I

• T cells (lymphocytes) bind to the surface of other cells (Antigen Presenting Cells) that display the antigen and trigger a response

Monocytes : Peripheral bloodMonocytes : Peripheral blood

Macrophages : TissuesMacrophages : Tissues

Dendritic cells : Lymphoid tissues Dendritic cells : Lymphoid tissues

Langerhans cells : EpidermisLangerhans cells : Epidermis

B-cells : Lymphoid tissue, Blood B-cells : Lymphoid tissue, Blood

Antigen Presenting cells that has MHC II

Macrophage

Lymphocyte

Lymphocyte

Cell Mediated Immunity

The T helper cell need the help from ( antigen presenting cell ) to recognize an antigen and produce an effect against that antigen

The APC ( antigen presenting cell ) hold the foregin antigen in one hand , and hold its MHC class in the other hand

Then it present both his MHC class and the foregin antigen to T helper cell in the same time

So T helper cell first recognize by MHC II that this is a normal body cell , then it recognize by the antigen that there is a foregin antigen having fun in the body that need to be killed so it produce a response against it

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5

6

Invariant chain(Ii)

In The Previous Picture

In ( 1 ) you can see a foreign body in red color havind a dark black part called the most antigenic part and that what stimulate T cells

In ( 2 ) the foreign body get endocytosed into an endosome

In ( 3 ) the endosome then fuse with the lysosome to degrade the antigen into small parts to separate the most antigenic part from the rest of it

In ( 4 ) the ER produce the MHC in vesicles that fuse with the endosome

In ( 5 ) the MHC work as a hand that hold the most antigenic part and present it to the T cell

In ( 6 ) the MHC and most antigenic part go to the surface of the cell and do the presentation to T cell

[ this process happen in both MHC class I and II cells ]

T cell ActivationAntigen Presentation

T cell Activation Antigen Presentation

CD4 ( T helper ) is the brain of the immune system

All effector cells work under its command

T lymphocytesCMI

Other cells

HI

If the antigen wes intracellul-ar the ( CMI ) will work , but if the antigen wes extracellu-lar the ( HI ) work

11 . Endogenous antigen . Endogenous antigen

2. E2. E xogenous antigen xogenous antigen

In viral infections like ( HIV ) , because the virus will inter the cell and force it to produce endogenous proteins for the virus so the foreign protein ( antigen ) come from inside the cell and that’s way it is called endogenous

Like microbes

Target cell Target cell

VirusVirus

Target cell Target cell

Target cell Target cell

The virus can not make its own proteins ( antigens ) so it need a host cell to produce its proteins ( endogenous antigens ) , the endogenous antigen will bind with ( MHC I ) of the effected cell and appear on the surface to be recognized by CD8 ( T cytotoxic ) to kill it

TranscriptionTranscriptionTranslationTranslation

Host cell Host cell

Viral protein

Target cell Target cell

Type of antigen Type of MHC Type of T cell

ExogenousExogenous MHC IIMHC II CD4CD4

EndogenousEndogenous MHC IMHC I CD8

Exogenous antigen like

MicrobesProteins

Cell-mediated immunity

Exogenous antigenExogenous antigen -CD4+ T lymphocyte -CD4+ T lymphocyte

ss (CD4 + cells) (CD4 + cells)

CMICMI

APCAPCAPCAPC

Antigen presenting cells

Monocytes/MacrophagesMonocytes/Macrophages

Dendritic cellsDendritic cells

Langerhans cellsLangerhans cells

B-cellsB-cells

APCAPCAPCAPC

Class II MHCClass II MHCClass II MHCClass II MHC

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Invariant chain(Ii)

- TCR MHC interaction- TCR MHC interaction

T cells

APC APC APC

Recognition No Recognition

T cells T cells

TCR TCR TCR

MHC MHC MHCX X Y

1 2 3

In the previous figure( there is an interaction between T cell receptor and MHC )

In ( 1 ) the MHC class is the right class for that T cell receptor and the picked up part of the foreign antigen is the most antigenic part , so there will be recognition and response to that antigen

In ( 2 ) the picked up part of the antigen is the most antigenic part , but the MHC class is not right for that T cell receptor , so there will not be a recognition and of course no response

In ( 3 ) the MHC class is right for that T cell receptor , but the picked up part of the antigen is not the most antigenic part , so no recognition and no response

So to have a recognition and response to an antigen by effected cells you need ( the right type of MHC , the right part of antigen ) to the TCR

Antigen presenting cell

4CD

TTT

T T T class

II

- CD4 MHC class II interaction

T cell

4CD

Antigen presenting cell Antigen presenting cell

4CD

T cell T cell

Cell-Mediated Immunity

• Lymphocytes: (B & T lymphocytes)

• B lymphocytes ("B cells"): These are responsible for making antibodies (humoral immunity)

• T lymphocytes ("T cells"): CMI• Subsets include:

– CD8+ cytotoxic T lymphocytes (CTLs) that kill virus-infected and tumor cells

– CD4+ helper T cells enhance CMI and production of antibodies by B cells

Cell-Mediated Immunity

• Examples of Cell-Mediated Immunity• Delayed-Type Hypersensitivity (DTH): the tuberculin

test (or Mantoux test) • Tuberculosis: a chronic disease, caused by

Mycobacterium tuberculosis• The response to tuberculin is called "delayed" because

cells take long time to arrive to site of infection • in contrast to the "immediate" responses characteristic of

many antibody-mediated sensitivities like an ( allergic response to a bee sting)

• So immediate hypersensitivity is mediated by humoral immunity , but delayed hypersensitivity and chronic diseases is mediated by cell mediated immunity

Cell Mediated Immunity

• DTH is a cell-mediated response

• Anti-tuberculin antibodies are rarely found in tuberculin-positive people

• The T cells responsible for DTH are members of the CD4+ subset

Cell-Mediated Immunity

• Contact Sensitivity• Many people develop rashes on their skin following

contact with certain chemicals such as nickel, certain dyes, and the active ingredient of the poison ivy plant

• The response takes some 24 hours to occur, and like DTH, is triggered by CD4+ T cells

• The actual antigen is probably created by the binding of the chemical to proteins in the skin

• The fragments of antigen are then presented to CD4+ T cells by phagocytic cells in the skin by antigen presentation

Activation of helper T cells

• Requires recognition of MHC - antigen complex on the surface of antigen-presenting cells eg, macrophages consisting of both antigen and class II MHC proteins

• Viral antigens are recognized in association with class I MHC proteins

• The activation of T cell in general by interaction between MHC – antigen complex and T cell receptor is called MHC restriction

Cellular Basis of Immune Response

• To activate T helper cell and initiate a response you need two signals ( 2 interactions )

• First signal • Interaction between ( Class II MHC + antigen )

with TCR• ] mediated by IL-1, LFA-1 with ICAM ( Inter-

Cellular Adhesion Molecule 1) [• Second signal (Co - stimulatory signal)

Interaction between B7 on APC with CD28 on T lymphocyte

The two reactions must happen to initiate the immune response

T helper cell

APC

CD28

B7

TCR

MHC

antigen

T cell Activation

• In the absence of co-stimulatory signal , state of unresponsiveness called “anergy” develops

• Production of co-stimulatory protein depends on activation of the toll like receptor on antigen presenting cell

• Foreign antigens such as bacterial proteins induce B7 protein where as self proteins do not

T cell Activation

• After antigen recognition by TCR, signal is transmitted through CD3 molecule ( receptor )

• This results in influx of calcium into the cell

• Calcium activates calcineurin

• Calcineurin activates gene for IL-2 and its receptor

Out come of T helper cell activation

• Production of IL-2 and its receptor– IL-2 is also know as T cell growth factor– Proliferation of antigen specific T cells– Effector and regulatory cells are produced

along with “memory” cells– IL-2 also stimulates CD8 cytotoxic cells

T helper cell

memory effector

Produce cytokines and activate other cells

Retain memory for different pathogens and proliferate in later exposure to that pathogen

Proliferateinto

Out come of T helper cell activation

• Production of Gamma Interferon (IF)

( IF is an antiviral substance that will kill cell infected by viruses and will make the cells resistant to viruses so virus can not enter to cells , ( used in hepatitis )

– It increases expression of Class II MHC proteins– It enhances the ability of APC to present antigen to

T cells– It enhances the microbicidal activity of macrophages– Enhances immune response

Out come of T helper cell activation

• Memory T cells• Respond rapidly for many years after initial

exposure to antigen• A large number of memory cells are produced so

that the secondary response is greater than the the secondary response is greater than the primaryprimary

• Memory cells live for many years and have the capacity to multiply

• They are activated by smaller amount of They are activated by smaller amount of antigenantigen

• They produce greater amounts of interleukinsThey produce greater amounts of interleukins

Effector functions of T cells

1. Delayed type of hypersensitivity mediated by Th-1 type of CD4 positive cells

2. Cytotoxicity: mediated by CD8 +ve cells.

Directed against virus infected cells, tumor cells and allografts

Killing by cytotoxic cells

– Perforins ( a chemical makes wholes in cell membrane

– Granzymes – degrading enzymes– Fas-Fas Ligand interaction - apoptosis– Antibody dependent cellular cytotoxicity– Immune surveillance– Allograft rejection

The mechanism by which CD8 cell deal with cells The mechanism by which CD8 cell deal with cells that have strange antigen on their surface is :-that have strange antigen on their surface is :-

1- secrete perforin which is a peptide that’s make wholes in cell membrane

2- secrete enzymes which lyse the cell membrane

3- secrete cytokines like ( TNF ) which destroy cell membrane

Killing Mechanisms of Cytotoxic T cells

perforin enzymes cytokines

Activation of B cells

• B cell functions as APC• Multivalent antigen binds to surface IgM• Cross links adjacent Ig molecules• Igs aggregate to form “patches” and migrate to

one pole to form a cap• Capped material is endocytosed • Antigen is processed and epitopes appear on the

cell surface in association with Class II MHC proteins