TC & TH Cells Flashcards
Cytotoxic T Lymphocytes
(CTLs)
Characteristics
- 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
Precursor CTLs
- Recently activated naïve CD8+ T-cells cannot kill due to insufficient granules
- Needs time to mature before effector functions active
Methods of CD8+ T-cell Activation
- 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.
- 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
CTL
Killing Mechanism
Selective serial killers.
Requires cell-cell contact.
Cells die by apoptotic death to prevent lysis and release of the pathogen.
- Fas/FasL pathway
- Ca2+ dependent
- “extrinsic”
- recruitment of “death domain” containing molecules
- caspase 8 ⇒ caspase 3
- 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
Apoptosis
CTLs kill via apoptosis.
Neutrophils, macrophages, and complement induce a necrotic death.
Natural Killer Cells
- 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
- IFN-α / IFN-β
Viral Infection
Timeline
- 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
- IFNα, IFN-β, and IL-12 activate NK 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
- Cytotoxic CD8+ T-cells specific for the virus generated
Missing Self Model
- 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
TH Cell Cytokine Function
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
TH Cell
Class Determination
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
Model of TH Cell
Cytokine Secretion
Comparison of TH Cell Profiles
TH1 Functions
Recognizes bacterial peptides:MHC II ⇒ activates macrophages.
TH2 Functions
Recognizes antigenic peptide:MHC II ⇒ activates B-cells.
TH17 Cells
- 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