Transcript 8-9-TCRs and T-cells

TCRs, T-cells and Tolerance
From Chapter 8
Sections A and C only
-- we’ll only briefly cover TCR genes
From Chapter 9
We’ll cover sections A – E selectively
Self-Test Questions:
Chapter 8
A2: 1 – 3
B1: 2
C: 1, 3, 4
A3: 2
B2-4: 1 - 3, 4, 5
Chapter 9
A1-2: 1, 4
B1-2: 1, 3, 4
C1-3: all
D: 3, 4
F: 1, 3
A3iii-iv: 1 – 5, 8
B3-4: 2 & 3
C4-5: 1, 3, 5
E. skip
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How are TCRs different than Antibodies?
-- lower affinity for AG
-- only bind to AG + MHC
-- smaller spectrum of AG bound
-- TCRs not secreted
Structure of the T-cell receptor
-- member of the Ig superfamily
-- 1 V and 1 C domain / peptide
α&β
or
γ&δ
chains
-- we won’t talk much about γδTCRs
Receptor affinity comparison
TCR 3D models
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How is TCR AG-binding diversity created?
Arrangement of gene segments similar to Ab
Other mechanisms of diversity
P & N additions
junctional flexibility
But no somatic mutation
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T-cell development
and activation
Chapter 9
AG-independent vs
antigen dependent development
Role of the thymus
Progenitor migration
Roles for epithelial cells and DCs
-- self tolerance
Not responsible for all intermediate stages
DN = CD8- CD4DP = CD8+ CD4+
TCRs, T-cells and Tolerance
SP = CD8+ CD4or CD8- CD4+
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How are MHC-restricted, selftolerant T-cells selected?
“Central tolerance”
Selection steps
1) for functional TCR
2) for MHC-restriction of TCR
3) for Self-tolerance of TCR
See animation of T-cell selection
Department of Biology,
Davidson College
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How does “Positive selection”
for MHC-restriction occur?
Acts upon DP -- CD4+CD8+ thymocytes
Must bind to MHC I or MHC II
-- or die through apoptosis!
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How does ‘negative selection’
for self-tolerance occur?
Testing for high affinity for
Self-antigens
-- expression of AIRE (autoimmune regulator gene)
-- macrophages and DCs
-- some auto-reactive T-cells escape
Most T-precursor cells
eliminated
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T-cell activation
The TCR-CD3
receptor signalling
Function of CD3
-- signal transduction
Function of CD8 & CD4
-- strengthen binding
-- triggers CD3
phosphorylation
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How are Naïve TH
& Tc cells activated?
TH Activation
1) Binding to MHC+Ag
-- triggers expression of CD40L on TH
2) Costimulation from DC
-- Cd40/CD40L triggers
B7 expression on DC
3) Cytokine stimulation
-- B7/CD28 triggers IL2 expression
-- autocrine stimulation
DC activation = “licensing”
-- now capable of activating Tc
Tc cell activation
-- has more constraints
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Aberrant TH activation
can compound
disease symptoms
“Superantigens”
Staphylococcus, Streptococcus,
HIV, etc
May activate 5% of all T-cells
Excess cytokine production
Sun-burn rash of Toxic-shock syndrome
Staph -- food poisonings
-- Toxic Shock syndrome
HIV – T-cell depletion
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How do CTLs Kill?
Perforin/Granzyme triggered
-- homologous with C9
Fas Pathway
Cytokine Triggered
All trigger apoptosis
through Caspase cascade
Garland
CTL-killing
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Activated TH cells have specialized functions
Main Target
Cells
Effector
Functions
Effector
Cytokines
Pathological
Effects
TH1
Macrophages,
licensing of
dendritic cells,
(Tc-cells)
Intracellular
pathogens
IFN-γ
Autoimmunity;
cell-mediated
allergies
TH2
Eosinophils,
basophils,
B cells
IgE against
extracellular
pathogens
IL-4
Asthma and IgEmediated allergies
TFH
B cells in
lymph node
follicles
Ig production against
extracellular
pathogens
IL-21
Autoimmune
diseases?
TH17
Neutrophils
Extracellular bacteria;
mediates inflammation
IL-17 &
IL-22
Autoimmune
diseases
Treg
T-cells,
B-cells,
Dendritic cells
Immunosuppression;
anti-inflammatory
IL-10
None?
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Correct T-cell type is critical to
effective immune response
Lepromatous Leprosy
TH1/TH2 imbalance
Mycobacterium leprae
Intracellular pathogen of macrophages
Tuberculoid form
Cell mediated response
TH1
Lepromatous form
Humoral response
TH2
-- lots of Ig, not very helpful
disfiguring granulomas form,
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Types of tolerance
Central vs Peripheral
Mechanisms of peripheral
tolerance
1. Missing signals, e.g.,
-- no TH help for B-cells or Tc cells
2. Treg cells
-- Immunosuppressive cytokines
3. Tolerogenic DC cells
-- induced by missing danger signals
Consequences
-- Cell anergization & apoptosis
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Various factors influence
tolerance
Dosage
History & frequency of exposure
Route of exposure
Subcutaneous
-- immunogenic at low dosages
-- desensitization therapy
Intravenous
-- less so
Oral
--tolerogenic at high dosages
The Microbiome
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Our Microbiota influence
Immune system function
Over 100 trillion cells
• ~90% of the cells in our body
• ~3 – 5 lbs of body weight
• 1000s of species
Discourage pathogens
Contribute to metabolism
Induce tolerance
• Suppress autoimmunity
& Inflammatory diseases
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Some tissues are
“Immune privileged”
e.g., eye, testis, brain, uterus
Immune suppressed
Mechanisms of tolerance
-- low MHC
-- immunosuppressive
hormones & cytokines
-- immune cell anergization
-- Fas-FasL
-- Tregs
-- etc
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