Lecture 14 & 15 (Linking V & VI) Flashcards
What are ways in which exogenous peptides can be presented on MHC class I and vice versa? (exceptions to the rules)
1) Cross-presentation
2) Presentation of cytosolic peptides by MHC Class II Molecules
3) Allorecognition
What is cross-presentation by dendritic cells (DCs)?
Cross-presentation by DCs involves the redirection of exogenous antigens into the endogenous presentation pathway, allowing them to be presented on MHC Class I molecules.
Which cells are capable of cross-presentation?
Dendritic cells (DCs) are the only antigen-presenting cells (APCs) known to exhibit cross-presentation.
Give an example of cross-presentation by DCs.
When dendritic cells (DCs) phagocytose virally infected cells, they process the viral antigens and present them on MHC class I molecules, activating CD8⁺ T cells. Normally, exogenous antigens are presented on MHC class II to CD4⁺ T cells, but cross-presentation allows DCs to bypass this rule and stimulate a CD8⁺ response against viruses that they themselves are not infected by.
What is the redirection mechanism of cross-presentation?
The actual redirection mechanism of exogenous antigens into the endogenous pathway is unclear, but it requires a “license” from activated CD4+ T cells.
What does it mean for a dendritic cell to be “licensed”?
A dendritic cell becomes “licensed” when it presents foreign antigen to a CD4+ T cell, which then provides cytokine and ligand signals, enabling the DC to redirect exogenous antigens into the endogenous pathway.
Why do dendritic cells need to be licensed to perform cross-presentation?
Activated CD4+ T cells provide the necessary signals (cytokines and ligands) to license dendritic cells, allowing them to present exogenous antigens on MHC Class I molecules and prime CD8+ T cell responses.
How are cytosolic peptides presented on MHC Class II molecules?
Cytosolic peptides can be presented on MHC Class II molecules through a process called autophagy, where the cell digests its own organelles and proteins in lysosomes.
What is an autophagosome?
An autophagosome is a specialized vesicle that contains cytoplasmic content and fuses with lysosomes to degrade the contents.
What are the steps involved in autophagy for MHC Class II presentation?
1) Parts of the cytoplasm are taken into autophagosomes.
2) Proteins in the autophagosomes are degraded.
3) The process links up to the exogenous pathway, allowing presentation on MHC Class II molecules.
Give an example of when autophagy is involved in MHC Class II presentation.
Some pathogens have adapted to resist intracellular killing, requiring macrophages to be stimulated by cytokines to kill these pathogens. These pathogens may also prevent presentation on MHC Class I, and autophagy helps present peptides on MHC Class II.
What does MHC restriction mean in T cell responses?
MHC restriction means a T cell can only recognize a specific peptide when it is bound to a specific self MHC molecule.
Can you give an example of MHC restriction?
Strain A animals only respond to antigens presented by strain A APCs but not by strain B APCs, due to MHC restriction.
What is allorecognition?
Allorecognition is the recognition of non-self MHC molecules (allo-MHC) by some T cells in the body. 1-10% of all T cells can react to allo-MHC.
Why is allorecognition important in transplantation?
Allorecognition is the main mechanism of rejection of transplanted organs between genetically different individuals of the same species.
What are the two types of allorecognition?
(1) Direct allorecognition: Recipient T cells recognize donor MHC molecules on the surface of donor cells.
(2) Indirect allorecognition: Recipient T cells recognize processed donor peptides presented by the recipient’s own APCs via self-MHC.
What is a gene?
A gene is a segment of a chromosome that controls a specific characteristic and encodes for a protein.
What is an allele?
An allele is a specific form of a gene.
What is a locus?
A locus is the specific chromosomal location of a gene.
What genes code for MHC molecules?
MHC molecules are coded by human leukocyte antigen (HLA) genes.
Where are MHC genes located?
MHC genes are located in a cluster on chromosome 6 in humans.
What are the two main classes of MHC genes?
1) MHC Class I genes: HLA-A, HLA-B, HLA-C
2) MHC Class II genes: HLA-DR, HLA-DQ, HLA-DP, HLA-DM, HLA-DOA, HLA-DOB
What is polymorphism?
Polymorphism refers to the existence of multiple variations (forms) or alleles for each gene.
How many alleles are there for many MHC genes?
Many MHC genes have more than 100 different alleles.
How are MHC alleles identified?
Alleles are identified by a number after the locus, e.g., HLA-A2, HLA-DR3.
What is a haplotype?
A haplotype is a particular combination of MHC alleles found on a single chromosome. Each individual inherits one haplotype from each parent.
How are MHC alleles expressed?
MHC alleles are codominantly expressed, meaning both maternal and paternal MHC genes are expressed in offspring cells.
What makes transplantation difficult?
MHC polymorphism makes transplantation difficult because humans are heterozygous at each locus, leading to diverse MHC expression.
What is polygeny?
Polygeny refers to having many copies of related genes, with each individual inheriting 3 MHC-I alleles from each parent (6 alleles total: one for HLA-A, HLA-B, and HLA-C per chromosome).
Where are differences found in the peptide binding groove of MHC molecules?
Differences are clustered at amino acid locations within the groove sites, allowing for the presentation of different varieties of peptides.
Why are changes outside of the peptide binding groove problematic?
If areas outside the groove are altered too much, it can affect the structure, conformation, and folding of the MHC molecule.
Can a given MHC molecule bind to multiple peptides?
Yes, a given MHC molecule can bind numerous different peptides, and some peptides can bind to different MHC molecules.
What are the main MHC Class I genes?
The main MHC Class I genes are HLA-A, HLA-B, and HLA-C.
What are the main MHC Class II genes?
The main MHC Class II genes are HLA-DR, HLA-DQ, HLA-DP, HLA-DM, HLA-DOA, and HLA-DOB.
What is the significance of polymorphism in MHC genes?
Polymorphism refers to the presence of multiple allelic variants of each MHC gene in the population, contributing to the diversity in peptide presentation.
How does allorecognition relate to MHC polymorphism?
Allorecognition is the ability of some T cells to recognize non-self MHC. The diversity from MHC polymorphism contributes to transplant challenges.
What is the characteristic of receptors with intrinsic kinase activity?
Receptors with intrinsic kinase activity have their own kinase activity and initiate signaling by dimerization and transphosphorylation.
How does signaling occur in receptors with intrinsic kinase activity?
Signaling is initiated by the dimerization of the receptor and the transphosphorylation of the receptor itself.
What is a key feature of extrinsic receptors?
Extrinsic receptors do not have intrinsic kinase activity but initiate signaling through the recruitment of kinases and dimerization, followed by transphosphorylation.
How does signaling occur in extrinsic receptors?
Signaling is initiated by the recruitment of kinases to the receptor, followed by dimerization and transphosphorylation.
What determines molecular interactions between proteins?
Molecular interactions are determined by domains in their structure that have selective binding properties, such as the SH2 domain.
What does the SH2 domain recognize?
The SH2 domain recognizes phosphorylated tyrosine (phosphotyrosines) on other proteins and is found in many proteins.
What are phosphotyrosines?
Phosphotyrosines are phosphorylated tyrosine residues that serve as binding sites for a number of protein-interaction domains.
What is the role of adaptor proteins in molecular interactions?
Adaptor proteins help form multimolecular complexes by interacting with other proteins, playing a crucial role in signaling pathways.
What are key post-translational modifications involved in signaling?
Phosphorylation and ubiquitination are key modifications that play important roles in protein function and signaling.
What is the role of kinases in signaling?
Kinases are proteins that phosphorylate other proteins, typically activating or regulating signaling pathways.
What do phosphatases do?
Phosphatases are proteins that dephosphorylate other proteins, often turning off signaling pathways.
What is the fate of ubiquitinated proteins?
Ubiquitinated proteins are targeted for degradation by the proteasome or lysosome.
How do phosphorylation and ubiquitination affect signaling?
Both phosphorylation and ubiquitination can function to activate or inhibit signaling, depending on the context.
Why is it important for signaling to be turned off?
Signaling must be turned off as well as turned on to prevent continuous activation, ensuring appropriate cellular responses.
What are the three signals required for optimal T-cell activation?
(1) Signal 1: pMHC:TCR engagement with coreceptor binding.
(2) Signal 2: Contact with costimulatory ligands.
(3) Signal 3: Cytokines directing T-cell differentiation into distinct effector cell types.
What components are involved in TCR binding and signaling initiation?
The TCR complex consists of:
- TCR
- ITAM domains (Immunoreceptor tyrosine-based activation motifs)
- CD3
- Zeta (ζ) chains
What happens when pMHC:TCR binding occurs with coreceptor binding?
When pMHC:TCR binding occurs and the coreceptor binds MHC:
Lck (Lymphocyte-specific protein tyrosine kinase) is recruited.
Lck phosphorylates the ITAMs, initiating more signaling.
Zap-70 is recruited to the ITAMs and is phosphorylated by Lck.
What role does Zap-70 play in TCR signaling?
Zap-70 binds to phosphorylated ITAMs, is phosphorylated by Lck, and activates many downstream signaling molecules, leading to transcriptional changes.
What is the main takeaway from Signal 1 in TCR signaling?
Signal 1 results in intracellular signaling:
- Lck is recruited and phosphorylates ITAMs.
- Zap-70 is recruited and binds to phosphorylated ITAMs, initiating signaling cascades.
- This leads to the transcription of many genes
What is the role of costimulation in T-cell activation?
Costimulation is required for T-cell activation, survival, and proliferation. Without it, T-cells may become unresponsive (anergic).
What are the key costimulatory ligands and receptors involved in T-cell activation?
1) Ligands on APCs:
CD80 (B7.1)
CD86 (B7.2)
2) Receptor on T cells:
CD28 (Positive costimulatory receptor)
What are the negative costimulatory receptors?
- CTLA-4
- PD-1
(These receptors help turn activation off.)
What happens when CD28 binds to B7 molecules (CD80/CD86)?
1) Binding to B7 molecules (CD80/86) triggers phosphorylation of CD28.
2) This activates a kinase, which leads to the recruitment of another kinase.
3) Additional signaling follows, facilitating T-cell activation.
What is clonal anergy and how does it occur?
- Clonal anergy occurs when T-cells become nonresponsive due to a lack of costimulation.
- This is important for regulation and to decrease the risk of autoreactive T-cells.
- Anergic T-cells can no longer respond to future stimulation.
