Lecture 12 & 13 (Linking innate III & IV)) Flashcards
What does the TCR recognize?
The TCR recognizes peptide-MHC (pMHC) complexes on the surface of antigen-presenting cells (APCs).
What is required for TCR recognition of pMHC?
T cell and APC contact is required, leading to the formation of an immunological synapse.
What are the components of the TCR complex?
The TCR complex includes:
TCR
CD3
Zeta (ζ) chain
ITAMs (Immunoreceptor tyrosine-based activation motifs)
What does ITAM stand for and what is its function?
ITAM stands for Immunoreceptor Tyrosine-Based Activation Motif. It plays a role in intracellular signaling when the TCR complex is activated.
What happens after TCR recognition of pMHC?
Intracellular signaling is triggered
What is the structural nature of the TCR recognition subunit?
It is a heterodimer of chains, transmembrane proteins, and not secreted.
What are the two main types of TCRs on mature T cells?
αβ TCR (most common)
γδ TCR (less than 10%)
What does “clonotypic” mean in relation to TCRs?
It means that all cells of a given T cell clone have identical TCRs.
What are the two key regions of a TCR?
1) Variable (V) region – responsible for antigen recognition
2) Constant (C) region – provides structural support
What happens to adaptive immune receptor genes in individual lymphocytes?
They undergo DNA rearrangement to generate diverse receptors.
How many adaptive immune receptors exist compared to innate immune receptors?
1) Billions of adaptive immune receptors (BCR & TCR)
2) 100 or fewer innate immune receptors
What gene segments are involved in adaptive immune receptor rearrangement?
Variable (V), Diversity (D), Joining (J), and Constant (C) gene segments.
What gene segments are present in the α and β chains of the TCR?
1) α chain: V, J, and C segments
2) β chain: V, D, J, and C segments
Where does TCR rearrangement occur?
In the thymus.
What is somatic recombination in T cells?
It is the rearrangement of gene segments in the TCR genetic loci to produce a functional TCR.
What does the TCR recognize?
The TCR recognizes the peptide in the context of MHC but does not recognize the peptide alone.
What are the types of antigen-presenting cells (APCs)?
1) Professional APCs – Dendritic cells (DCs), macrophages, and activated B cells
2) Non-professional APCs – All nucleated cells in the body
What do professional APCs express?
1) MHC class I and class II molecules
2) Costimulatory molecules (when activated)
What do non-professional APCs express?
1) MHC class I molecules (under normal conditions)
2) Do NOT express MHC class II or costimulatory molecules
Why are there two classes of MHC molecules?
To cover two main types of pathogens:
1) Intracellular pathogens → MHC Class I
2) Extracellular pathogens → MHC Class II
What type of peptides do MHC Class I molecules present?
Endogenous peptides (generated within the cell), including self-proteins.
What type of peptides do MHC Class II molecules present?
Exogenous peptides (originating from outside the cell).
Which type of T cell does MHC Class I activate?
CD8+ T cells (cytotoxic T cells).
Which type of T cell does MHC Class II activate?
CD4+ T cells (helper T cells).
What are the components of an MHC Class I molecule?
- α chain (transmembrane)
- β2-microglobulin (non-transmembrane, invariant, binds noncovalently)
- α chain has three domains
What are the components of an MHC Class II molecule?
- α chain + β chain (both transmembrane)
- Each chain has two domains
What three components are needed for stable expression of MHC molecules?
- MHC Class I: Peptide + MHC Class I α chain + β2-microglobulin
- MHC Class II: Peptide + MHC Class II α + MHC Class II β chains
What structural feature do MHC chains share with many immune system molecules?
Immunoglobulin (Ig)-like domains, which have:
- ~100 amino acids
- α helices and β strands
- Stabilization by intrachain disulfide bonds
What are the key structural features of the MHC peptide-binding groove?
- Faces outward for antigen presentation
- More conserved region faces the cell membrane
- Allele-specific differences are mainly in the peptide-binding cleft
- Both MHC I and II peptide-binding grooves have α helices and β sheets
How long are the peptides bound by MHC Class I molecules?
8–10 amino acids (short, tightly bound within the cleft).
How long are the peptides bound by MHC Class II molecules?
At least 13 amino acids (length is not constrained).
What are the key structural components of the pMHC-TCR interaction?
- MHC at the bottom
- Peptide in yellow (inside the cleft)
- TCR on top, with key domains in various colors
Why are co-receptors needed in TCR-pMHC interactions?
Because TCR-pMHC interaction has low affinity, co-receptors (CD4/CD8) enhance binding.
What are the structural features of the CD4 co-receptor?
Single-chain transmembrane protein
Four Ig-like domains
What are the structural features of the CD8 co-receptor?
- Heterodimer (two chains linked by disulfide bond)
- Each chain has one Ig-like domain
- Both chains are transmembrane proteins
What are the two main functions of CD4 and CD8 co-receptors?
- Bind to MHC molecules → Enhance TCR-pMHC interaction affinity
- Initiate TCR signaling (Signal 1)
What type of processing does Class I antigen presentation require?
Class I antigen presentation requires cytosolic or endogenous processing.
What type of processing does Class II antigen presentation require?
Class II antigen presentation requires exogenous processing.
What is the difference between Class I and Class II antigen presentation pathways?
Class I: Cytosolic or endogenous processing.
Class II: Exogenous processing
What type of pathogens are presented on MHC Class I?
Endogenous pathogens, such as viruses, intracellular bacteria, and intracellular parasites.
Where are endogenous pathogens degraded for MHC Class I presentation?
They are degraded in the cytosol.
What cells recognize peptides presented on MHC Class I?
Effector CD8 T cells.
What process generates peptides for MHC Class I presentation?
Proteins are tagged with ubiquitin and degraded by proteasomes.
What role does polyubiquitination play in antigen processing?
Polyubiquitination serves as a signal for proteasomes to recognize and degrade proteins.
What happens to polyubiquitinated proteins in the proteasome?
They are bound by the 19S cap, degraded in the catalytic core, and peptides are released into the cytosol.
Does MHC Class I present only pathogen-derived peptides?
No, it also presents self-peptides due to the constant turnover of proteins and cells.
What holds the partly folded MHC Class I alpha chain in place during Step 1?
The chaperone calnexin holds the MHC Class I alpha chain in place.
Is beta-2 microglobulin bound to MHC Class I in Step 1?
No, beta-2 microglobulin is not yet bound.
What happens to MHC Class I in Step 2?
- MHC Class I is released from calnexin.
- The MHC I alpha chain interacts with beta-2 microglobulin and additional chaperones (calreticulin, ERp57).
- The partly folded MHC Class I binds to the chaperone tapasin, which links it to TAP.
What is happening in the cytosol during Step 2?
Proteins are being translated, and some are being ubiquitinated.
What happens to polyubiquitinated proteins in Step 3?
Polyubiquitinated proteins are degraded by the proteasome in the cytosol.
How are peptide fragments brought into the ER in Step 3?
Peptide fragments are transported into the ER by TAP.
What does ERAAP do to peptides in Step 3?
ERAAP trims peptides that are too long to bind to MHC Class I.
What happens when peptides bind to MHC Class I in Step 3?
Peptide binding allows MHC Class I to fold properly.
What happens in Step 4?
- The peptide binds to the peptide-binding groove of MHC Class I.
- MHC Class I folding is complete.
- The peptide-MHC Class I complex (pMHC-I) is released from TAP and targeted to the cell surface.
How are exogenous pathogens taken up by immune cells?
Exogenous pathogens are taken up by immune cells through phagocytosis or endocytosis.
What types of pathogens are processed via the MHC Class II pathway?
Extracellular bacteria, parasites, and fungi are processed via the MHC Class II pathway.
What happens to pathogens once they are inside immune cells?
Pathogens are degraded in endocytic vesicles, and peptides are generated to bind to MHC Class II for presentation.
What immune cells are involved in MHC Class II presentation?
Macrophages and B cells are involved in MHC Class II presentation to effector CD4 T cells.
Where are peptides generated in the exogenous pathway?
Peptides are generated in acidified endocytic vesicles.
What happens to endosomes during the exogenous pathway?
Endosomes fuse with lysosomes (e.g., phagolysosomes), where the pathogen contents are degraded.
How are MHC Class II molecules produced?
MHC Class II molecules are produced in the ER and transported in vesicles.
What is the role of invariant chain (Ii) in MHC Class II processing?
- Ii binds to the peptide groove of MHC Class II to prevent premature binding of peptides.
- Ii guides MHC Class II molecules to endocytic vesicles.
- Ii uses sorting signals in its cytoplasmic tail to direct MHC Class II-containing vesicles to peptide-containing endocytic compartments.
What happens to invariant chain (Ii) in the endocytic compartments?
Ii is degraded by proteolytic activity to form Class II-associated invariant chain peptide (CLIP).
What prevents peptides from binding to the MHC Class II groove in the ER?
The invariant chain (Ii) prevents premature peptide binding in the ER.
What is the role of invariant chain (Ii) in MHC Class II processing in Step 1?
Invariant chain (Ii) binds to MHC Class II, preventing peptides from binding. This occurs in the ER and endocytic vesicle.
What happens to the invariant chain (Ii) in Step 2?
The invariant chain (Ii) is degraded due to acidification, leaving CLIP bound to the MHC Class II molecule.
What occurs in Step 3 during MHC Class II processing?
The vesicle containing degraded peptides fuses with the MHC Class II-containing vesicle, but peptides still cannot bind to MHC Class II because CLIP is blocking the groove.
What is the function of HLA-DM in Step 4?
HLA-DM binds to MHC Class II, stabilizes it, and releases CLIP from the peptide-binding groove.
What happens after CLIP is released in Step 4?
After CLIP is released, peptides can bind to the peptide-binding groove of MHC Class II.
What happens to the peptide-MHC Class II complex after peptide binding?
The peptide-MHC Class II complex (pMHC-II) is targeted to the cell surface.
