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
T regulatory cell
Function
- Role in inducing peripheral tolerance
- Prevents immune responses against self-Ag or commensal microorgansims
- Generates inhibitory cytokines
Treg Cell Induction
- 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
Treg Cell
Mechanism
Expresses both CD4 and CD25 (α-subunit of IL-2R).
Produces IL-10 and TGF-β.
Treg cells inactivate traditional T cells by:
- Cytokine deprivation by binding to IL-2 in the microenvironment
- Generation of inhibitor cytokines like TGF-β
- Inhibiting APCs
- Cytotoxicity
Th Cell Class Summary

Thymic Indepedent B-cell Activation
- 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
T-independent B cell Responses
- 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
Thymic Dependent B-Cell Activation
- B-cell binds its Ag
- Ag cross-linking of surface Ig activates B cell
- Induces B cell proliferation
- IgM synthesis
- Surface Ig also facilitates receptor-mediated endocytosis leading to presentation of peptides from Ag on B cells MHC II
- T-cell with same Ag specificity binds peptide/MHC II (TCR:MHC/peptide and CD28:B7) on B-cell promoting T-cell activation
- Allows Th2 cell to signal B cell through:
- CD40:CD40L interaction
- cytokines
- Leads to B cell proliferation, Ab synthesis, and isotype switching
- After ~ 1 week, germinal centers formed in secondary lymphoid organs
- Activated B cells undergo somatic hypermutation and affinity maturation within GC
- Development of memory B cells largely dependent on T cell help
T-dependent B-cell Response
- 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

Ig Class Switching
- 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

Summary of T-B Collaboration
- 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