Exam 1: T-cell Types and Functions

Question 1

Cytotoxic T Lymphocytes (CTLs)

Characteristics

Answer 1

• Recognize Ag in class I MHC-restricted manner
• Kills infected cells or those expressing “altered-self” Ag
• Can make IL-2, IFN-α, and TNF-α
• Major role in defense against viral infections and malignant cells
• Causes damage during autoimmune diseases or transplant rejection

Question 2

Precursor CTLs

Answer 2

• Recently activated naïve CD8⁺ T-cells cannot kill due to insufficient granules
• Needs time to mature before effector functions active

Question 3

CD8⁺ T-cell

Activation

Answer 3

1. T_H - cell independent
   
   • APC (Dendritic cells) ⇒ licensed/active APC
   • MHC-I+Peptide and costimulation signal (B7-1 or B7-2)
   • APC signal must be strong enough to stimulate CD8⁺ T-cells to produce IL-2
2. T_H - cell dependent (most effective)
   
   • T_H cell with same TCR specificity helps
   • Upregulates co-stimulatory molecules on APC’s (B7-1)
   • Produces IL-2 which helps activate CTL

Question 4

CTL

Killing Mechanism

Answer 4

Selective serial killers.

Requires cell-cell contact.

Cells die by apoptotic death to prevent lysis and release of the pathogen.

1. Fas/FasL pathway
   
   • Ca²⁺ dependent
   • “Extrinsic” path
   • Recruitment of “death domain” containing molecules
   • Caspase 8 ⇒ ⊕ caspase 3
2. Performin/granzyme pathway
   
   • Pore can form on plasma membrane or endosomes
   • Ca²⁺ independent
   • “Intrinsic” path
   • Apaf-1 and procaspase-9 ⇒ ⊕ caspase 9
   • ⊕ effector caspase 3 by cleavage

Question 5

Apoptosis

Answer 5

CTLs kill via apoptosis.

Neutrophils, macrophages, and complement induce a necrotic death.

Question 6

NK Cells

Answer 6

• Large lymphocytes that participate in the innate immune response
• Defense against viruses and malignant cells
• Activated by:
  
  • IgG leading to ADCC
  • Lack of class I MHC on target cell
• Kills via:
  
  • Perforin and granzyme
  • Fas:FasL
• Secretes IFN-γ and TNF-α
• Stimulated by:
  
  • IFN-α / IFN-β
    
    • From virus-infected cells
    • Favors development of cytotoxic effector function
  • IL-12
    
    • Made by macrophages
    • Favors IFN-γ production by NK cells (and Th1 cells)
      
      • Acts as a positive feedback loop further activating macrophages

Question 7

Viral Infection

Timeline

Answer 7

• Early during a viral infection:
  
  • IFN-α, IFN-β, and IL-12 ⇒ NK cell activation
  • NK Cells
    
    • Produces most of the IFN-γ
    • Provides most of the cytotoxicity against infected cells
• Later on in the infection:
  
  • Cytotoxic CD8⁺ T-cells specific for the virus generated
    
    • Becomes the main IFN-γ producers
    • Becomes the main anti-viral cytotoxic cell

Question 8

Missing Self Model

Answer 8

• Normal cells present a ligand for the activating and inhibitory receptors (MHC I) on NK cells
• When viruses infect cells, some may inhibit MHC class I expression to evade CTLs
• Makes them prime target for elimination by NK cells
• NK cells recognize and kill infected and tumor cells by absence of MHC class I

Question 9

T_H Cell

Cytokine Function

Answer 9

Helps to select which immune effector mechanisms engaged:

• CD8⁺ cell proliferation and activation
• Macrophage activation
• NK cell activation
• B cell proliferation, activation, and isotype switching

Question 10

T_H Cell

Class Determination

Answer 10

1. Initial local cytokine environment during T-cell activation and development
2. Self-promoting regulation
3. Cross-regulation between classes

Question 11

T_H1 Cell

Induction

Answer 11

• Functions through T-bet transcription factor
• ⊕ by IL-12 and IFN-γ
• ⊗ by IL-10

Question 12

T_H2 Cell

Induction

Answer 12

• Functions through GATA3 transcription factor
• ⊕ by IL-4

Question 13

T_H Cell

Self-Promoting Regulation

Answer 13

• T_H1 cells
  
  • IFN-γ ⇒ ⊕ T-Bet ⇒ ↑ IFN-γ
• T_H2 cells
  
  • IL-4 ⇒ ⊕ GATA-3 ⇒ ↑ IL-4 & IL-5

Question 14

T_H Cell Class

Cross-Regulation

Answer 14

• T_H2 cells produce:
  
  • IL-10 ⇒ ⊗ TH1 pathway
  • IL-4 ⇒ down-regulates T-bet ⇒ inhibits IFN-γ effects
• T_H1 cells produce:
  
  • IFN-γ ⇒ down-regulates GATA-3 ⇒ ⊗ TH2 pathway

Question 15

Model of T_H Cell

Cytokine Secretion

Answer 15

Question 16

Comparison of T_H Cell Profiles

Answer 16

Question 17

T_H1 Functions

Answer 17

Recognizes bacterial peptides:MHC II ⇒ activates macrophages.

Question 18

T_H2 Functions

Answer 18

Recognizes antigenic peptide:MHC II ⇒ activates B-cells.

Question 19

T_H17 Cells

Answer 19

• Proinflammatory cells
• Generated early in immune response when mature microbe-activated dendritic cells make high levels of IL-23, IL-6, and TGF-β which stimulate naive CD4+ T-cells
• Down-regulated to IFN-γ or IL-4 (Th1 or Th2 response)
• Produces IL-17 and IL-6:
  
  • ⊕ neutrophil recruitment
  • ⊕ fibroblast/epithelial cell cytokine production
• Role in bacterial and fungal defense

Question 20

T_reg Cell

Function

Answer 20

• Role in inducing peripheral tolerance
• Prevents inappropriate immune responses against self-Ag or commensal microorgansims
• Down regulation of immune responses

Question 21

T_reg Cell

Induction

Answer 21

• In absence of infection
  
  • Dendritic cells make TGF-β >> IL-6
  • Continue to present self & environmental Ag
  • Continue to deliver Ag to lymph nodes
• Naive CD4⁺ T-cell stimulated by a dendritic cell producing high TGF-β but no other cytokines involved in T_H cell differentiation
  
  • Leads to expression of transcription factor FoxP3
  • Results in T_reg cell generation
  • Deficiency in FoxP3 causes absence of Treg ⇒ IPEX disease

Question 22

T_reg Cell

Mechanism

Answer 22

Expresses both CD4 and CD25 (α-subunit of IL-2R).

Produces IL-10 and TGF-β.

T_reg cells inactivate traditional T-cells by:

• Cytokine deprivation
  
  • CD25 binds IL-2 with low affinity ⇒ no activation
• Generation of inhibitory cytokines ⇒ TGF-β
• Inhibiting APCs
• Cytotoxicity

Question 23

Th Cell Class Summary

Answer 23

Question 24

Thymic Indepedent B-cell Activation

Answer 24

• T-cell indepedent Ag
  
  • Ex. polysaccharides, lipopolysaccharides, and proteoglycans with repetitive epitopes
• Able to activate naive and/or mature B cells without activating T cells
• Without T-cell help:
  
  • ↓ isotype switching
  • ↓ somatic mutation
  • ↓ memory development
• Age dependent

Question 25

Thymic-independent

B cell Responses

Answer 25

• Primary, quick response
  
  • Lower concentrations of Ab
  • IgM >>>> all other Ig classes
    
    • Agglutination & complement activation
• Secondary responses mostly absent
  
  • Memory T-cells not involved
• Speed of innate w/ specificity of adaptive

Question 26

Thymic Dependent

B-Cell Activation

Answer 26

1. B-cell binds Ag
   
   • B-cell activation and proliferation
   • IgM synthesis
2. B-cells present Ag peptides on MHC II to T-cells
   
   • Via Ig receptor-mediated endocytosis
3. T-cell with same Ag activated
   
   • TCR : MHC+peptide
   • CD28 : B7
4. Allows T_h2 cell to signal B-cell through:
   
   • CD40 : CD40L interaction
   • Cytokines
5. Leads to B cell proliferation, Ab synthesis, and isotype switching
6. After ~ 1 week, germinal centers formed in secondary lymphoid organs
7. Activated B cells undergo somatic hypermutation and affinity maturation
8. Development of memory B cells largely dependent on T-cell help

Question 27

Thymic-dependent

B-cell Response

Answer 27

• Slower initiation
  
  • Both T & B need to be stimulated then find each other
  • Both T & B need to recognize similar Ag
• Longer lasting
  
  • Memory exists in both B and T
• Quicker response on subsequent exposure
  
  • Due to permanent changes secondary T and B
• Isotype switching occurs
• Majority of Ag induce thymic-dependent B-cell activation
  
  • Basis for vaccine modification using T-cell dependent Ag to stimulate both

Question 28

Isotype Switching

Answer 28

• In primary response, CD4⁺ T-cells already activated by dendritic cells or macrophages
• Interaction between T and B cells dependent on:
  
  • TCR recognition of peptide + MHC Class II on B cell
  • B cell Ag processing via Ig receptor mediated endocytic route
    
    • Better than Mφ at targeted immune response
  • Processed Ag and re-expressed peptides in context of MHC II
  • Optimal response when both epitopes on same molecular complex allowing cell-cell contact
• Co-Stimulatory signals required
  
  • CD28 (T cells) : B7 (B cells)
  • CD40 ligand (T cells) : CD40 (B cells)
    
    • Defect ⇒ Hyper-IgM Syndrome

Question 29

Summary of T-B Collaboration

Answer 29

• B cell and T cell in 2° lymphoid tissue
• Both bind same Ag and Ag present ⇒ interact
• T cells make cytokines that B cells need for:
  
  • B cell activation, proliferation, differentiation
    
    • IL-2, IL-4, IL-6
  • Isotype switching
    
    • IL-4 ⇒ IgE (allergy)
    • IL-10 and TGF-β ⇒ IgA
  • Affinity maturation
  • Memory B cell development