TC & TH Cells Flashcards

1
Q

Cytotoxic T Lymphocytes

(CTLs)

Characteristics

A
  • 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
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2
Q

Precursor CTLs

A
  • Recently activated naïve CD8+ T-cells cannot kill due to insufficient granules
  • Needs time to mature before effector functions active
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3
Q

Methods of CD8+ T-cell Activation

A
  1. TH - cell independent
    • APC (Dendritic cells) ⇒ licensed/active APC
    • MHC-I/Peptide + costimulation signal (B7-1 or B7-2)
    • APC signal must be strong enough to stimulate CD8+ T-cells to produce IL-2.
  2. TH - cell independent (most effective)
    • TH cell with same TCR specificity helps
    • Upregulates costimulatory molecules on APC’s (B7-1)
    • Produces IL-2 which helps activate CTL
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4
Q

CTL

Killing Mechanism

A

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”
    • 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”
    • Apaf-1 and procaspase -9 ⇒ caspase 9
    • Activate effector caspase (3) by cleavage
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5
Q

Apoptosis

A

CTLs kill via apoptosis.

Neutrophils, macrophages, and complement induce a necrotic death.

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6
Q

Natural Killer Cells

A
  • Large lymphocytes that participate in the innate immune response
    • Keeps you alive during the primary 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
  • Makes 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
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7
Q

Viral Infection

Timeline

A
  • Early during a viral infection:
    • IFNα, IFN-β, and IL-12 activate NK cells
      • Produce 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
      • Become the main IFN-γ producers
      • Become main anti-viral cytotoxic cell
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8
Q

Missing Self Model

A
  • Normal cells present a ligand for the activating and inhibitory receptors (MHC I) to 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
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9
Q

TH Cell Cytokine Function

A

Helps to select the immune effector mechanisms engaged:

  • CD8+ cell proliferation and activation
  • macrophage activation
  • NK cell activation
  • B cell proliferation, activation, and isotype switching
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10
Q

TH Cell

Class Determination

A

Initial local cytokine environment at the time of T-cell activation, proliferation, and differentiation critical in determining subset created.

  • IL-12 and IFN-γ favors TH1 cells.
  • IL-4 favors TH2 cells.
  • IL-10 inhibits TH1 pathway thus indirectly promotes TH2 production.
  • Most immune reponses include both subclasses.

Self-Promoting Regulation:

  • IFN-γ ⇒ STAT1 ⇒ T-Bet ⇒ Increased IFN-γ
  • IL-4 ⇒ STAT6 ⇒ GATA-3 ⇒ Increased IL-4 & IL-5

Cross-Regulation:

  • TH2 cells produce:
    • IL-10 ⇒ down-regulates TH1 cells
    • IL-4 ⇒ down-regulates T-bet
  • TH1 cells produce:
    • IFN-γ ⇒ down-regulates TH1 cells by decreasing GATA-3
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11
Q

Model of TH Cell

Cytokine Secretion

A
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12
Q

Comparison of TH Cell Profiles

A
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13
Q

TH1 Functions

A

Recognizes bacterial peptides:MHC II ⇒ activates macrophages.

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14
Q

TH2 Functions

A

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

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15
Q

TH17 Cells

A
  • 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:
    • Induce neutrophil recruitment
    • Induce fibroblast/epithelial cytokin production
  • Role in bacterial and fungal defense
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16
Q

T regulatory cell

Function

A
  • Role in inducing peripheral tolerance
  • Prevents immune responses against self-Ag or commensal microorgansims
  • Generates inhibitory cytokines
17
Q

Treg Cell Induction

A
  • In absence of infection, dendritic cells make TGF-β > IL-6.
    • Continue to present self & environmental Ag
  • Naive CD4+ T cell stimulated by dendritic cell producing high TGF-β but no other cytokines involved in Th cell differentiation
    • Leads to transcription factor FoxP3
    • Results in Treg cell generation
    • Deficiency in FoxP3 causes absence of Treg = IPEX disease
18
Q

Treg Cell

Mechanism

A

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

Produces IL-10 and TGF-β.

Treg cells inactivate traditional T cells by:

  1. Cytokine deprivation by binding to IL-2 in the microenvironment
  2. Generation of inhibitor cytokines like TGF-β
  3. Inhibiting APCs
  4. Cytotoxicity
19
Q

Th Cell Class Summary

A
20
Q

Thymic Indepedent B-cell Activation

A
  • Thymic (or T cell) indepedent Ag able to activate naive and/or mature B cells without activating T cells
  • Tend to be polysaccharides, lipopolysaccharides, and proteoglycans with repetitive epitopes
  • Without T-cell help, there is little isotype switching, somatic mutation, or development of memory
  • Age dependent
21
Q

T-independent B cell Responses

A
  • Primary, quick response
  • Lower concentrations of Ab
  • IgM >>>> Ig anything else
    • Agglutination & complement activation
  • Typical secondary responses largely do not happen because memory T cells not involved
  • Speed of innate w/ specificity of adaptive
22
Q

Thymic Dependent B-Cell Activation

A
  1. B-cell binds its Ag
    • Ag cross-linking of surface Ig activates B cell
    • Induces B cell proliferation
    • IgM synthesis
  2. Surface Ig also facilitates receptor-mediated endocytosis leading to presentation of peptides from Ag on B cells MHC II
  3. T-cell with same Ag specificity binds peptide/MHC II (TCR:MHC/peptide and CD28:B7) on B-cell promoting T-cell activation
  4. Allows Th2 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 within GC
  8. Development of memory B cells largely dependent on T cell help
23
Q

T-dependent B-cell Response

A
  • 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
24
Q

Ig Class Switching

A
  • In primary response, CD4+ T-cells are already activated by dendritic cells or macrophages.
  • Interaction between T and B cells is dependent on:
    • TCR recognition of peptide + MHC Class II on B cell
    • B cell has internalized Ag through recognition of Ag by surface Ig receptor-endocytic route
      • Better than macrophages 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 on T cells and B7 on B cells
    • CD40 ligand on T cells and CD40 on B cells
      • Defect = Hyper-IgM Syndrome
25
Q

Summary of T-B Collaboration

A
  • B cells meet T cells in secondary lymphoid tissue
  • If they recognize the same antigen and if that antigen is present, they interact.
  • T cells make cytokines that the B cell needs to become activated, switch their isotypes,
  • become memory B cells, and improve the affinity of their antibody
  • The main effects of cytokines produced by activated T cells on B cells
  • IL-2, IL-4, IL-6 lead to B cell activation, proliferation, differentiation
  • Isotype switching is dependent on the cytokine produced by the T cell
  • IL-4 - role in switching to IgE (allergy)
  • IL-10 and TGFβ - role in switching human B cells to make IgA