CellMediated Immune Response

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Chapter 5

• Cell-Mediated Immune Response

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Cell-Mediated Purpose

• Combat infection of intracellular microbes
• virally infected cells have virus replicating
  inside the cytoplasm
• phagocytes that pick up microbes but they are
  resistant to destruction, grow in vesicles or
  cytoplasm
• Removal mediated by T-lymphocytes in adaptive
  immune system
• CD4 helper T-cells help B-cells make Ab (other
  arm of adaptive immune response)
• must interact with other cells such as
  phagocytes, infected host cells or B-cells
• specific for MHC class for the type of T-cell

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Types of Intracellular Microbes
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Phases of T-Cell Response

• Sequential steps that result in increase in the
  numbers of Ag-specific T-cells and conversion of
  naïve T-cells to effector cells
• Naïve T lymphocytes circulate looking for Ag,
  express the receptor but cant perform the
  effector function
• must be stimulated to differentiate into effector
  cell (T-helper/CTL) initiated by Ag recognition
• done in peripheral lymphoid tissue
• also gets signals from microbes and/or innate
  immune system

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Phases (cont)

• Combination of all signals cause Ag-specific
  T-cells to secrete cytokines
• happens to CD4 and CD8 cells
• cytokine and Ag and microbe act as 2nd signal
  that causes proliferation to increase the numbers
  of Ag-specific T-cells
• called CLONAL EXPANSION
• fraction undergoes differentiation and switch
  functions from recognizing Ag to effector T-cells
  to eliminate microbes
• as microbe is eliminated, effector T-cells die
  and return to basal level of lymphocytes

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Phases of Activation
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Effects (CD4/CD8)
Stay in LN to Kill
Some leave the LN and migrate to site of
infection to help eliminate the microbe
Help B-cells make Ab by passing signal on to
B-cell
Develop into memory T-cells mostly inactive,
circulate until encounter Ag again months to
years later
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Ag Recognition and Costimulation

• 3 categories, each with distinct functions
• adhesion
• recognition
• signaling
• Requires multiple receptors on T-cell recognizing
  APC
• TCR peptide/MHC
• CD8 or CD4 MHC
• adhesion molecules on T-cell APC
• receptors for costimulators for 2nd signal from
  APC
• Anything other than TCR are accessory molecules
• invariant among T-cells

Know the molecule and ligand
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MHC-Associated Peptide Recognition

• Initiation signal TCR and CD8 or CD4 receptor
  recognize peptide-MHC on APC
• cytosolic proteins MHC I CD8 CTL
• vesicular proteins MHC II CD4 helper
• TCR recognizes peptide and AA residues on MHC
  around peptide binding cleft
• CD4 and CD8 are co-receptors on MHC-restricted
  T-cell help to bind TCR to MHC
• recognize at sites separate from the peptide
  binding site that helps to ensure the correct
  T-cell response
• Must get 2 or more TCR and co-receptors to bind
  MHC-peptides to initiate the signaling pathways
• must encounter an array of Ag for a long time or
  multiple times to begin the activation
  threshold needed to initiate response

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Biochemical Signals

• T-cell activation requires proteins linked to TCR
  to form TCR complex and to CD4or CD8 coreceptor
• 2 set of molecules
• Ag receptors with much diversity
• those that are conserved signals
• TCR recognizes the Ag but cant pass on the
  signal so TCR associates with CD3 (complex of 3
  proteins) and with a homodimer of ? chain
• now signal can be passed to the interior of the
  T-cell

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TCR Complex

• Made up of TCR (?/? chains) that recognizes
  antigen and CD3 and ? chains carry out the signal
  function
• TCR that are made up of ?/? chain are found in
  the epithelium and dont recognize MHC-peptide
  complexes but lipids and other microbial
  compounds protect from common epiletial
  pathogens

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Unusual T-Cell Activation

• There are chemicals that can bind TCR of many or
  all T-cell clones regardless of peptide
• polyclonal activators are used to study
  activation, diagnosis diseases of T-cells
  function, etc
• Ab to TCR or CD3 carbohydrate molecules like
  phytohemagglutinin super Ag (microbial protein)
• Microbial super Ag can cause a huge T-cell
  response and excess release of cytokines that can
  make the host very sick

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Adhesion Molecules Functions

• Recognize ligands on APC and stabilize binding of
  T-cell to APC
• TCRMHC binding usually has low affinity
• probably due to selection process
• must maintain contact until signaling threshold
  is achieved
• Most important molecules are the INTEGRINS
  heterodimeric proteins
• Leukocyte Function-Associated Ag-1 (LFA-1) on
  T-cell binds Intracellular Adhesion Molecule-1
  (ICAM-1) on APC

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Integrin Avidity

• On naïve T-cell, LFA-1 is in a low affinity state
• Exposure to chemokines from the innate immune
  response to Ag allows for the expression of high
  affinity state clusters within minutes of
  TCRMHC binding
• tight at infection site and is a positive
  feedback loop
• Integrins also aid in directing migration of
  effector T-cells (Chapter 6)

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Role of Costimulators

• Full T-cell activation requires costimulators on
  the surface of APC provide stimuli to T-cell
• 2 best defined are B7-1 (CD80) and B7-2 (CD86)
• both are on professional APC and their expression
  is increased when in contact with microbe
• B7 molecules recognize CD28 expressed on nearly
  all T-cells essential for activating T-cells
• ensures full activation of naïve T-cells
• other costimulator molecules that may function to
  activate or for negative regulators of T-cell
  may function to activate or regulate effector
  T-cells
• CD40L on T-cells and CD40 on APC not a direct
  enhancement of T-cell activation
• causes the expression of more B7 molecules and
  activates APC to secrete cytokines
• IL-12 enhances T-cell proliferation and makes APC
  better APC

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Costimulation of T-Cells

• TCRMHC-peptide is not enough may lead to
  T-cell unresponsiveness ANERGY naïve T-cell
  recognize Ag but no co-stimulators
• Use adjuvants to help get a T-cell dependent
  immune response in vaccines
• microbial proteins that stimulate macrophages and
  other APS
• Understand T-cell activation may have clinical
  aplications
• B7CD28 and CD40LCD40 inhibitors are in clinical
  trials to block graft rejection
• may eventually be used in tumor biology

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Activation of CD8 T-Cells

• Activation of CD8MHC-peptide require
  costimulation and/or helper T-cells
• CD8 CTL in some viral infections require
  concomitant activation of CD4 helper T-cell
• cross presentation with Ag for MHCI/MHCII
• both CD4 and CD8 cells can be activated by 1
  dendritic cells
• CD4 cell may produce cytokines or membrane
  molecules to help activate CD8 cells clonal
  expansion of T-cell and differentiation into
  effector/memory CTL
• may explain CLT deficiency to virus infection in
  HIV and patients because of lack of CD4 (cell
  death by HIV)
• Not all viral infection require CD4 help to make
  CTL

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Response

• Response of T-lymphocytes to Ag and
  constimulation are mediated by cytokines that are
  secreted by the T-cell and acts on T-cells as
  well as other cells of the immune system

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Cytokine Activity

• Secretion of cytokines and the expression of
  cytokine receptors
• Response to costimulators and Ag
• especially CD4 cells secrete several different
  cytokines with many activities
• effector CD4 cells secrete other cytokines
• Cytokine function as mediators of immunity and
  inflammation
• innate immunity macrophage secrete
• adaptive immunity T-cells secrete
• some similarities but also distinct and have
  different roles in the immune response

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KNOW THIS!!!!!
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KNOW THIS!!!!
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IL-2 and T-Cell Activation

• 1-2 hours after CD4 cells IL-2 is secreted which
  enhances the ability of T-cells to respond to
  IL-2 by way of regulation of IL-2 receptor
  expression
• IL-2 receptor has 3 protein chains, naïve T-cells
  express 2 of the 3 proteins (??c) which cant
  bind IL-2 with high affinity
• 3 chains (???c) gets expressed after activation
• now have receptor that can strongly bind IL-2,
  preferentially on the same T-cell
• IL-2 stimulates T-cell proliferation forces
  cells into cell cycle
• acts as a T-cell growth hormone
• CD8 T-cell doesnt appear to make large
  amounts IL-2, may depend on CD4 helper cells to
  provide IL-2

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IL-2 Interactions