Chapter 4: Antigen Recognition by B-cell and T-cell Receptors Flashcards
What are B cells? Where do they mature? What types are there? What is additional function they can serve?
- Lymphocyte that matures in bone marrow
- involved in hummoral immunity
- Naive B cells (have not encountered antigen)
- Effector cells (plasma cells that produce Ig)
- Memory B cells
- Also function as antigen presenter cell
Where do T cells mature? How do they recognize antigens? What are the types of T cells?
- Thymus
- TCR recognize antigens presented on a MHC molecule
- Naive has not encountered antigen
Effector cells - Helper (CD4+): cytokines, recog MHC II
- Cytotoxic (CD8+): cytotoxins, recog MHC I
- Regulatory: control immune reaction, inhibit T cells
Memory T cells
What are four effector modules and what do they do?
- Cytotoxicity, Intracellular immunity, Mucosal barrier, Extracellular immunity
What do ILCs do?
- Function as effector cells in innate immunity to amplify signals delivered by innate recognition
- Similar to T cells
- Cytokines signal for innate lymphoids which make effector molecules to carry out a function
What do cytokines and interferons do?
- Activate NK cells
- IL-12,-18 stimulate NK cells to release IFN- γ
- Activation of NK cells contains virus while adaptive immune response makes antigen specific T cells and antibodies
- Also produce TNF, GM-CSF, chemokines
How do NK cells kill?
- Release cytotoxic granules similar to T cells containing perforin and granzymes which induce apoptosis
- Antibody dependent cell mediated cytotoxicity (ADCC) is when NK FC receptors recognize antibodies which induce the release of granules
- TRAIL (Tumor necrosis factor related apoptosis inducing ligand) pathway
- TRAIL inceracts with TNFR (DR4 DR5) which activate caspase 8 leading to apoptosis
How do NK cells differentiate between healthy and infected cells?
- Activating (activate cytotoxic activity) and inhibitory (suppress cytotoxic) receptors
- NK cells recognize the balance between receptors and act accordingly
What are the four types of recognition NK cells can make?
- Normal healthy cells
- Express activating ligands (inhibitory > activating)
- high MHC I
- Missing self
- Absence of MHC I
- Activating signal not suppressed (inhibitory < activating)
- Stress induced self
- Increased expression of activating (inhibitory «activating)
- Infectious non-self
- Expression of activating ligands encoded by infectious agents (inhibitory < activating)
What is the structure of an antibody?
- Immunoglobins (Ig) are Y shaped proteins
- 2 heavy chains, 2 light chains connected by disulfied bonds
- 2 regions, Variable varries, constant is relatively conserved bt Ig
- Hinge links Fc and Fab
Describe the domains of an immunoglobulin.
Heavy chain: 4 domains
- 3 constant (CH1-3) and 1 variable (VH)
Light chain: 2 domains
- 1 Constant (CL) and one variable (VL)
- Each domain made of two folded beta sheets and covalent bonded by disulfied bond
What can papain or pepsin do to an antibody?
- Can be readily cleaved into functionally distinct fragments
What role does the hinge region play in flexibility?
- Hinge region allows for binding to multiple antigens
- Hinge flexibility enables Fab region to move freely
How are different classes of immunoglobulins distinguished?
- Distinguished by the structure of thei heavy-chain constant region
- 5 major isotypes/classes: IgG,M,A,D,E
- IgG: IgG1,2,3,4 IgA: IgA1,A2
- Differ by number of C domains, location and # of disulfied bonds,# N linked carbs
- Fc receptors may say which antibody it binds to
- Fcγ binds IgG
What do the constant regions of an antibody confer with? What do IgM and G do? What are the effector functions of Fc region
- Constant regions confers function specialization
- IgM: first antibody from B cell IgG: most common in serum (crosses placenta)
- Fc receptor binding, complement activation, regulation of secretion
How are antibodies transported?
- Fc portion binds to receptors that actively transport antibody through cell
- IgA into mucous, tears, breast milk (pIgR)
- IgG mother -> fetus (FcRn)
What is the importance of hypervariability?
- Forms antigen binding site
- Rest of V domain is framework region
- Sequenced variability in three segments
- Heavy: 30-36, 49-65, 95-103
- Light: 28-35, 50-56, 91-98
What is a benefit of hypervariability sequences being closely positioned to one another?
- Allow for complementary determing regions (CDRs) which compliment the antigen
How are antibodies able to bind to antigens?
- Complementary determining regions (CDRs) complement size and shape of antigen
What role do non-covalent interactions play in antibody binding?
- Electrostatic, H, Van der Waals, Hydrophobic, Cation pi
How do steric constraints influence antibody binding?
- Even if antibody has high affinity sometimes the binding of an antibody can prevent another from being able to bind
- Ex. West Nile virus
Describe the T cell receptor.
- Similar to Fab of Ig
- Heterodimer (alpha beta) bound by disulfied bonds
- Contain 3 CDRs in Variable domain, fourth in hypervariability domain (away from antigen)
- TCR dimer forms multiprotein complex with 6 polypeptides that do signal transduction (CD3, chain)
Describe three properties of TCRs.
- One antigen binding region
- Never secreted
- Basic residues required for assembly
What relationship do TCR and MHC have with each other?
- TCR recognize antigens presented to them by MHC receptors
Describe MHC I.
- 2 Polypeptides
- Alpha chain(3 domains)
- Beta - microglobulins
- Peptide binding cleft
Describe MHC II
- 2 polypeptides
- alpha domain (2 chains)
- beta domain (2 chains)
- Peptide binding cleft
What is the benefit of different MHC molecules?
- Allow for binding of different peptides
- Polymorphism, Polygeny, Codominant expression
- People have different MHC molecules that also differ from person to person
Discuss polygeny in MHC molecules?
- MHC genes on chromo 6 (HLA)
- Different genes code for different MHC molecules of same class (isotype)
- 3 MHC I genes = 3 different MHC I isotypes (HLA-A,-B,-C)
- 3 MHC II genes =3 different isotypes (DQ,DP,DR)
How many alleles are there for HLA? What is codominance?
- There are two alleles, one maternal and one paternal
- MHC alleles are polymorphic (many diff in the population)
- Both alleles are expressed equally and 3 are from dad 3 are from mom
What is cross combination?
- When alpha and beta chains from different alleles combine leading to MHC II combinations
- DQ from mom can swap with DQ from dad
How do peptides binding to MHC molecules affect it?
- Peptides bond stability and stabilize cell surface
Describe the kind of binding that can occur for MHC class I molecules.
- Bind short peptides (8-10 residues)
- stabilizes complex by binding peptide
- Anchor residues on peptide allow for specificity (No anchor, no binding)
Are anchor residues the same amino acids as those in different MHC I molecules?
- Anchor residues differ in amino acids and position of different MHC I variants
- Similar it peptides within the same variant
Describe the binding constraints by MHC class II molecules.
- 13< aa length, usually 13-17
- Peptide ends not bound
- Peptide binds along the length of the binding groove
- Also anchor residues like MHC I
Do T cell receptors always bind in the same orientation to MHC complex?
- THe usually do bind in a similar orientation with the TCR over the peptide
How do CD4 and CD8 proteins send a signal to MHC to elicit a response?
- CD4 CD8 surface proteins (from T cell) come in direct contact with MHC to respond to antigen
-Increase sensitivity of T cells to antigen x100 - CD8 recognizes MHC I
- CD4 recognizes MHC II
- Coreceptors bind to MHC away from the peptide binding site
Describe the structure of CD4 and how it binds to MHC II.
- Single chain protein
- D(omain)1,2 are tightly packed like a rod, Hinge lings D1,2 to D3,4
- Lateral face of D1 binds to hydrophobic crevice at junction of A2B2 domains of MHC II
Describe the structure of CD8 and how it binds to MHC I.
- Dimer composed of alpha and beta linked by disulfied bond
- Linked to membrane by glycosylated polypeptide
- ** CD8 binds to invariant loop site in A3 domain of MHC I**
What is the effect of interferons on MHC molecule expression?
- Type I increases the expression of MHC I
- Type II increases the expression of MHC II
What do surface markers on leukocytes do?
Help identify:
- Cell lineage and subsets within lineage
- Stage of maturation
- State of cell activation
- Markers can have receptor, ligand, or structural functions
- Cells can gain or lose markers
