L18 March 20 Dr Choy Immune System Flashcards
Describe the fxn of the two types of T cells and what they bind to
T cells – recognize specific short peptides (9 – 11 aa for CD8 T cells, ~20 aa for CD4 T cells) in the context of major histocompatibility complex (MHC) molecules.
– Binding is mediated by T cell receptor (TCR)
– CD8 T cells bind peptide in the context of MHC class I
• Kills cells that express the peptide-MHC class I
– CD4 T cells bind peptide in the context of MHC class II
• Secrete cytokines
Describe fxn of B cell
B cells – bind to proteins through B cell receptor (BCR) which is antibody bound to B cell membrane – Activation results in secretion of antibodies – Antibodies bind to proteins in tissues and either kill cells associated with them or activate inflammation
Describe the antigen processing to its display on the cell surface
- The epitopes recognized by T cell receptors are often buried
- The Ag must be 1st broken down into peptide fragments
- The epitope peptide bind to a self molecule, MHC molecule
- The TCR binds to a complex of MHC molecule and epitope peptide
How do peptides wind up on MHC I molecules on the cell surface?
- Production of proteins in the cytosol
- Proteolytic degradation of proteins
- Transport of peptides from cytosol to ER
- Assembly of peptide-class I complexes in ER
- Surface expression of peptide-class I complexes
How do peptides wind up on MHC II molecules on the cell surface?
- Uptake of extracellular proteins into vesicular compartments of APC
- Processing of internalized proteins in endosomal/lysosomal vesicles
- Biosynthesis and transport of class II MHC molecules to endoscopes
- Association of processed peptides with class II MHC molecules in vesicles
- Expression of peptide-MHC complexes on cell surface
What are the 5 routes of Ag processing by dendritic cells? Type of pathogen presented? MHC molecule loaded? Type of naive T cell activated?
- Receptor mediated phagocytosis
- a) Type of pathogen presented: Extracellular bacteria
- b) MHC molecule loaded: MHC class II
- c) Type of naive T cell activated: CD4 T cells - Macro-pinocytosis
- a) Type of pathogen presented: Extracellular bacteria, soluble antigens, virus particles
- b) MHC molecule loaded: MHC class II
- c) Type of naive T cell activated: CD4 T cells - Viral infection
- a) Type of pathogen presented: Viruses
- b) MHC molecule loaded: MHC class I
- c) Type of naive T cell activated: CD8 T cells - Cross-presentation after phagocytic or macropinocytic uptake
- a) Type of pathogen presented: Viruses
- b) MHC molecule loaded: MHC class I
- c) Type of naive T cell activated: CD8 T cell - Transfer from incoming dendritic cell to resident dendritic cell
- a) Type of pathogen presented: Viruses
- b) MHC molecule loaded: MHC class I
- c) Type of naive T cell activated: CD8 T cell
Describe the pathway of Ag being taken up by dendritic cell to where it activates T cells
- Ag uptake by Langerhan cells in skin
- Langerhan cells leave skin and enter lymphatic system
- Mature dendritic cells enter lymph node from infected tissues and can transfer some Ags to resident dendritic cells
- B7 pos dendritic cells stimulate naive T cels
What Three Signals Are Needed to Activate T Cells (delivered by APCs)
Signal 1: TCR binding to peptide MHC
The following two are absent normally but induced by inflammation:
Signal 2: Co-stimulatory molecule expression on antigen presenting cell and binding to partner on T cell
Signal 3: Cytokine secretion by APC
What occurs when TCR binding to peptide-MHC (signal 1) only (ie. without signal 2)
Results in no activation or inhibition of activation
Describe fxn of CD8 T cells
- CTL recognizes and binds virus-infected cell
- CTL programs target for death, including DNA fragmentation. E.g. release cytotoxic vesicles containing granzymes and perforin.
- CTL migrates to new target
- Target cell dies by apoptosis
Fxn of Treg?
- Inhibit the activity of effector T cells
– By doing so prevent immune rxms against Ags
– Essential for preventing immune rxns to self Ags that cause autoimmunity
- Maintain tolerance to self antigens
What are the 2 types of Treg?
Natural T regs and induced T regs
What % of CD4 T cells do natural Treg make up? Where do natural Tregs develop?
– 5-15% of circulating CD4 T cells
– CD4-positive, FoxP3-positive, CD25-high
– Develop in thymus towards self-antigen
How does peripherally induced Fox3-Pos Tregs (induced T regs) induced?
– Induced in the periphery from naïve precursors
– Induced by TGFβ
Describe the mechanisms of suppression of T cells
- Can be antigen-dependent or independent
- can act in the periphery or in lymph nodes
– Direct suppression of T cells • Soluble factors – Eg. IL-10, TGFβ • Cytotoxicity – Granzyme B • Expression of inhibitory surface proteins – Eg. CTLA4 • Generation of adenosine which is immunosuppressive • Depletion of bioavailable IL-2 – Modulation of DC function • Cell contact dependent – recognizes self antigen-MHC • Secretion of IL-10 and TGFβ • Spatial modulation of immune responses – Inhibition of dendritic cell migration to lymph nodes
Describe the self regulation of T cell activation by co inhibitory molecule CTLA4
• Induced late after T cell activation
- Binds B7s with much higher affinity than CD28
- Transduces inhibitory signals to prevent T cell activation
How do Abs secreted by plasma B cells aid in immune response
- Neutralization
- Abs prevent bacterial adherence - opsonization
Ab promotes phagocytosis - Complement activation
- Ab activates complement, which enhances opsonization and lyses some bacteria
What are the steps in Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)
- Ab binds Ags on surface of target cells
- Fc receptors on NK cells recognize bound Ab
- Cross linking of Fc receptors signals NK cell to kill target cell
- Target cell dies by apoptosis
Describe the Regulation of NK Cell Activation
- MHC class I on normal cells is recognized by inhibitory receptors that inhibit signals from activating receptors
- NK cell doesn’t kill normal cell
- Altered or absent MHC class I can’t stimulate a neg signal. The NK cell is triggered by signals from activating receptors
- Activated NK cell releases granule contents, inducing apoptosis in target cell
What are the 3 immunological components most directly relavent for cancer immunotherapy?
- T cells
– CTLs and maybe CD4 T cells that kill tumors - NK cells – kill tumors
- Antibodies
– Target tumors
– Neutralize tumorigenic processes
– Target immunoregulatory processes
What is the Immune Response Towards Tumors
- Tumors often infiltrated by T cells, NK cells and macrophages
- Abs to some tumor Ags can sometimes be observed
- Abundance of lymphocytes in tumors sometimes associated with better prognosis
Describe the mouse experiment that demonstrates the immune system protects against cancer
Based on the transplantation (via injection) of tumor cells into mice – Must be done into MHC matched strains otherwise allogeneic rejection occurs • When injected, most tumor cells grow and kill the host • If mice are injected with irradiated tumor cells (to prevent cell proliferation) prior to injection with non-irradiated tumors, they are often protected • This protection is not seen in T cell-deficient mice and can be conferred by adoptive transfer of T cells from immunized mice
Describe the specificity of anti-tumor response. What are tumor rejection Ags?
Tumor rejection antigens: Peptides of cellular proteins bound to MHC molecules on the tumor cell surface • There is specificity of the immune system for cancer type. Irradiated tumor X cells do not provide protection against tumor Y
Evidence that Immunosuppression in People Can Lead to Expansion of Cancer
One report in which 2 people got kidney transplants from the same donor – Donor had a previous, successfully treated, malignant melanoma • Likely had undetectable melanoma cells in kidney at time of transplant • Both recipients developed melanoma after transplantation – Immunosuppression prevented the control of the melanoma by the host immune system
