TCRs, T-cells and Tolerance 1

TCRs, T-cells and Tolerance

From Chapter 8Sections A and C only-- we’ll only briefly cover TCR genes

From Chapter 9We’ll cover sections A – E selectively

Self-Test Questions:Chapter 8A2: 1 – 3 A3: 2B1: 2 B2-4: 1 - 3, 4, 5C: 1, 3, 4Chapter 9A1-2: 1, 4 A3iii-iv: 1 – 5, 8B1-2: 1, 3, 4 B3-4: 2 & 3C1-3: all C4-5: 1, 3, 5D: 3, 4 E. skipF: 1, 3

TCRs, T-cells and Tolerance 22

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

TCR 3D models

Receptor affinity comparison

TCRs, T-cells and Tolerance 33

Other mechanisms of diversityP & N additionsjunctional flexibility

But no somatic mutation

How is TCR AG-binding diversity created?

Arrangement of gene segments similar to Ab

TCRs, T-cells and Tolerance 44

T-cell development and activationChapter 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 stagesDN = CD8- CD4- DP = CD8+ CD4+ SP = CD8+ CD4-

or CD8- CD4+

TCRs, T-cells and Tolerance 55

How are MHC-restricted, self-tolerant 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 selectionDepartment of Biology,

Davidson College

TCRs, T-cells and Tolerance 66

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!

TCRs, T-cells and Tolerance 77

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

TCRs, T-cells and Tolerance 88

T-cell activation

The TCR-CD3 receptor signalling

Function of CD3-- signal transduction

Function of CD8 & CD4-- strengthen binding-- triggers CD3 phosphorylation

TCRs, T-cells and Tolerance 9

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

TCRs, T-cells and Tolerance 1010

Aberrant TH activation can compounddisease symptoms

“Superantigens”

Staphylococcus, Streptococcus, HIV, etc

May activate 5% of all T-cells

Excess cytokine production

Staph -- food poisonings -- Toxic Shock syndrome

HIV – T-cell depletion

Sun-burn rash of Toxic-shock syndrome

TCRs, T-cells and Tolerance 1111

How do CTLs Kill?

Perforin/Granzyme triggered-- homologous with C9

Fas Pathway

Cytokine Triggered

All trigger apoptosis through Caspase cascade

GarlandCTL-killing

TCRs, T-cells and Tolerance 1212

Activated TH cells have specialized functions

Main Target Cells

Effector Functions

Effector Cytokines

Pathological Effects

TH1Macrophages, licensing of

dendritic cells, (Tc-cells)

Intracellular pathogens IFN-γ

Autoimmunity;cell-mediated

allergies

TH2Eosinophils, basophils,

B cells

IgE against extracellular pathogens IL-4 Asthma and IgE-

mediated allergies

TFHB 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

TregT-cells,B-cells,

Dendritic cells

Immunosuppression; anti-inflammatory IL-10 None?

TCRs, T-cells and Tolerance 1313

Correct T-cell type is critical to effective immune response

Lepromatous Leprosy

TH1/TH2 imbalance

Mycobacterium leprae

Intracellular pathogen of macrophages

Tuberculoid formCell mediated responseTH1

Lepromatous formHumoral responseTH2

-- lots of Ig, not very helpfuldisfiguring granulomas form,

TCRs, T-cells and Tolerance 1414

Types of tolerance

Central vs Peripheral

Mechanisms of peripheraltolerance

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

TCRs, T-cells and Tolerance 1515

Various factors influence tolerance

Dosage

History & frequency of exposure

Route of exposureSubcutaneous

-- immunogenic at low dosages-- desensitization therapy

Intravenous-- less so

Oral --tolerogenic at high dosages

The Microbiome

TCRs, T-cells and Tolerance 16

Our Microbiota influenceImmune 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

TCRs, T-cells and Tolerance 1717

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