Cell Mediated Immunity (CMI) Immune team

Cell-Mediated Immunity (CMI) Antigen T-lymphocytes Immune responses Immune 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 blood Macrophages : Tissues Dendritic cells : Lymphoid tissues Langerhans cells : Epidermis B-cells : Lymphoid tissue, Blood Antigen Presenting cells that has MHC II

Macrophage 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

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 Activation Antigen Presentation

CD4 ( T helper ) is the brain of the immune system All effector cells work under its command

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

1. Endogenous antigen 2. Exogenous 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 Virus

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

TranscriptionTranslation Host cell Viral protein Target cell

Type of antigenType of MHCType of T cell Exogenous MHC II CD4 Endogenous MHC I CD8

Exogenous antigen like Microbes Proteins Cell-mediated immunity

Exogenous antigen CD4+ T-lymphocytes (CD4+ cells) CMI CMI APCAPC Antigen presenting cellsMonocytes/Macrophages Dendritic cells Langerhans cells B-cells APCAPC Class II MHC

Invariant chain(Ii)

TCR-MHC interaction T cells APC Recognition No Recognition T cells TCR MHC X X Y 123

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 CD4 TCR MHC class II CD4-MHC class II interaction T cell CD4 Antigen presenting cell CD4 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 memoryeffector Produce cytokines and activate other cells Retain memory for different pathogens and proliferate in later exposure to that pathogen Proliferate into

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 the secondary response is greater than the primaryA large number of memory cells are produced so that the secondary response is greater than the primary Memory cells live for many years and have the capacity to multiply They are activated by smaller amount of antigenThey are activated by smaller amount of antigen 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 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 enzymescytokines

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