Lecture 19: T Cells II Flashcards
What are Fas ligand and CD40 ligand, and when are they expressed?
- Both are transmembrane ligands in the TNF family.
- They are expressed on the surface of effector T cells (not on naïve T cells).
- Their expression is induced by signals 1, 2, and 3.
- They are crucial for cell-to-cell interactions and effector T cell function.
Which cells express Fasligand and what is its function?
(1) Expressed on: Effector CD8+ T cells and TH1 cells.
(2) Function:
- Used by CD8+ T cells to exert cytotoxic effects.
- Binds to Fas on the surface of infected cells at the site of infection, triggering cell death.
Which cells express CD40 ligand and what role does it play?
(1) Expressed on: TH1, TH2, TH17, and TFH cells.
(2) Function:
- Binds to CD40 on B cells and innate immune cells.
- Activates target cells, promotes DC licensing, and increases the expression of co-stimulatory molecules.
What are the three signals required to activate naïve CD8+ T cells into effector CTLs?
(1) Signal 1: TCR binds peptide presented by APC on MHC class I.
(2) Signal 2: Costimulatory signal via CD28-B7 (CD80/86) interaction between the T cell and APC.
(3) Signal 3: Cytokines (mainly IL-2 and to some extent IL-12) induce proliferation and differentiation into CTLs.
What are the unique requirements and considerations for CD8+ T cell activation?
(1) Higher Co-stimulation: CD8+ cells require more robust co-stimulatory signals.
(2) IL-2 Production: IL-2 can be produced autocrine by the CD8+ T cell itself or paracrine from TH1 or TH17 cells.
(3) CD4+ T Cell Help: They require assistance from effector CD4+ T cells for optimal activation.
How do cytotoxic T lymphocytes (CTLs) recognize and kill target cells?
(1) Recognition: CTLs use their TCR to identify antigenic peptides presented by MHC I on infected or tumor cells.
(2) Killing: Once recognized, CTLs exert cytotoxic effects to eliminate these target cells.
What are the different ways CD8+ T cells can be activated to become cytotoxic effector cells?
(1) Direct Activation: (Rare) By activated dendritic cells that express high levels of co-stimulatory molecules (notably in some viral infections).
(2) CD4+ T Cell–Assisted Activation:
CD4+ effector T cells help license dendritic cells to cross-present antigens, providing the necessary signals for CD8+ T cell activation.
What is the difference between sequential and simultaneous interactions of APCs with CD4+ and CD8+ T cells?
(1) Sequential:
- APC first interacts with a CD4+ T cell, becomes licensed via CD40 signaling, and later interacts with CD8+ T cells independently.
(2) Simultaneous:
- APC interacts with both CD4+ and CD8+ T cells at the same time, receiving CD40 signals from CD4+ T cells and IL-2 from both cell types to enhance CD8+ T cell activation.
How does CD40 signaling contribute to APC (or DC) licensing?
CD40 Signaling:
- Triggered by the binding of CD40L (expressed on activated CD4+ T cells) to CD40 on the APC.
- Enhances APC function by:
(1) Increasing expression of co-stimulatory molecules (e.g., CD80/CD86).
(2) Promoting cross-presentation of exogenous antigens on MHC Class I.
(3) Inducing production of cytokines like IL-12.
What must occur in CD4+ T cells for effective CD8+ T cell activation?
- Recognize their specific antigen presented on MHC Class II (finding their p:MHC Class II match).
- Receive all three activation signals.
- Express CD40L to engage CD40 on the APC.
- Secrete IL-2 to support T cell proliferation.
What needs to happen for DCs to present antigen to both CD4+ and CD8+ T cells?
The DC must:
(1) Encounter a PAMP, prompting maturation.
(2) Migrate to a secondary lymphoid organ (e.g., lymph node).
(3) Present antigen on MHC Class II to activate CD4+ T cells.
(4) Become licensed via CD40 binding.
(5) Cross-present exogenous antigen on MHC Class I to activate CD8+ T cells.
How does IL-2 contribute to CD8+ T cell proliferation in sequential versus simultaneous activation scenarios?
(1) Sequential Activation:
IL-2 produced by CD8+ T cells alone drives their proliferation.
(2) Simultaneous Activation:
IL-2 is secreted by both CD4+ and CD8+ T cells, providing a more robust proliferative signal for CD8+ T cells.
What are the key events in CD4+ T cell activation that impact APC licensing?
(1) Upon activation, CD4+ T cells:
- Secrete IL-2.
- Express CD40L.
(2) This interaction licenses APCs, leading to:
- Enhanced co-stimulatory molecule expression (e.g., CD80/CD86).
- Induction of additional costimulatory ligands such as 4-1BBL (binding 4-1BB) and CD70 (binding CD27).
- Increased production of IL-12, further aiding CD8+ T cell activation.
Why is CD4+ T cell help important for generating memory CD8+ T cells?
CD4+ T cell help is critical for memory formation in CD8+ T cells, likely through:
- The additional cytokines they secrete (beyond IL-2).
- Their role in licensing APCs, ensuring optimal activation conditions for sustained CD8+ T cell responses.
How does a naïve CD8+ T cell become a CTL, and what is its next step after differentiation?
- A naïve CD8+ T cell receives activation signals and differentiates into a cytotoxic T lymphocyte (CTL).
- The newly formed CTL leaves the lymph node and travels to the site of infection.
How do CTLs identify their target cells in the periphery?
(1) CTLs use their TCR (with CD8 co-receptor) to interact with peptide–MHC Class I (pMHC I) complexes on target cells.
(2) All nucleated cells express MHC Class I, allowing CTLs to scan for infected or cancerous cells.
(3) Initial contact is mediated by nonspecific adhesion molecules.
(4) If the pMHC does not match the CTL receptor, the CTL moves on.
What happens when a CTL recognizes a target cell?
Upon recognition of a matching pMHC I, the CTL triggers cell death of the infected or cancerous cell via cytotoxic mechanisms.
What are the key effector functions of Cytotoxic T Lymphocytes (CTLs)?
Inducing apoptosis in infected or cancerous cells via:
(1) Fas-FasL mediated killing
(2) Granule-mediated killing
- secreting cytokines to direct the broader immune response.
How do CTLs use the Fas-FasL pathway to kill target cells?
Effector CTLs express Fas ligand (FasL) on their surface.
Target cells express Fas on their membranes.
Binding of FasL to Fas initiates a signaling cascade that:
- Cleaves pro-caspases into active caspases
- Leads to apoptosis of the target cell.
Describe the process of granule-mediated killing by CTLs.
(1) Initial Contact: CTLs make contact with the target cell via nonspecific adhesion molecules.
(2) Specific Recognition: The TCR on CTLs binds to the peptide-MHC Class I complex on the target cell.
(3) Cytoskeletal Reorganization: The CTL reorganizes its cytoskeleton, directing cytoplasmic granules (containing perforin and granzymes) to the point of contact.
(4) Granule Release: Granules are exocytosed at the contact point, delivering their contents to induce apoptosis in the target cell.
How do CTLs use granules to induce apoptosis in target cells?
- CTLs release granules containing perforin and granzymes upon TCR recognition of pMHC on a target cell.
- Perforin forms pores in the target cell membrane.
- Granzymes (serine proteases) enter the target cell through these pores, initiating apoptosis by cleaving pro-caspases into active caspases, leading to DNA fragmentation and cell death.
What is the sequence of events from CTL activation to target cell apoptosis via the perforin/granzyme pathway?
(1) TCR Engagement: CTL TCR binds pMHC on the target cell, triggering intracellular signaling.
(2) Cytoskeletal Reorganization: The CTL reorganizes its cytoskeleton to direct granules toward the contact site.
(3) Granule Release: Perforin is released and forms pores in the target cell membrane.
(4) Granzyme Entry: Granzyme B enters the target cell cytoplasm through these pores.
(5) Apoptotic Signaling: Granzyme B cleaves pro-caspases to caspases, leading to DNA fragmentation, membrane blebbing (observed ~40 minutes later), and apoptosis.
How do the perforin/granzyme and Fas–FasL pathways differ in CTL-mediated killing?
(1) Perforin/Granzyme Pathway:
- Fast-acting mechanism.
- CTLs primarily use this pathway to quickly induce apoptosis.
(2) Fas–FasL Pathway:
- Slower mechanism.
- Involves CTL-expressed FasL binding to Fas on the target cell, triggering a caspase cascade over a longer time.
(3) Combined Action:
- Both mechanisms converge on caspase-3 activation and can work simultaneously to enhance CTL lytic action.
- This dual strategy allows CTLs to kill infected or tumor cells while sparing neighboring uninfected cells.
