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Immunology > TBL 2 > Flashcards

TBL 2 Flashcards

1
Q

How many T cells do you need to recognize the pathogen peptides?

A

~10^13

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2
Q

How are the correct number of TCRs created?

A 
Somatic recombination (randomly form the antigen recognition part of the TCR) - genome is NOT large enough to encode that number of genes
Selection mechanism to eliminate clones that overtly recognize self
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3
Q

How do we prevent microbial pathogens from outsmarting the MHC system?

A

Diversify - peptide-presenting MHCs vary from individual to individual
Multiple loci for MHC within an individual - increase number of different MHC structures
HLA-A, HLA-B, HLA-DR… Etc
(HLA = Human Leukocyte Antigens)

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4
Q

How do we get just the right MHC that recognize self and antigen differently?

A

Colonial selection process centered in the thymus
Select the repertoire of clones with TCR appropriate for the self-MHC and self-peptides of each individual
Non-reactive against self (“tolerance”)
Reactive against non-self (“immunity”)
2 steps in thymic education:
1. Select T cell clones that recognize self-peptide in own MCHC molecules (positive selection)
2. Delete overtly self-reactive clones w/ high affinity for self-peptide MHC (negative selection; central tolerance)

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5
Q

What is the basis of graft rejection?

A

Immunologic “self”

Different MHC alleles in donor and patient

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6
Q

How do MHC differ for viruses and extracellular bacteria?

A

Viruses - viral peptide on cell’s MHC means that T cell should kill infected cell

Bacteria - bacterial peptide on a phagocytic cell signifies that the phagocyte has ingested a foreign substance and must be helped by the activated T cell to eliminate the pathogen

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7
Q

What is the difference between MHC I and MHC II?

A

MHC I: On any nucleated cell that has been virus or pathogen infected; peptide presented on MHC I molecule means KILL

MHC II: On a macrophage/DC or B cell that has phagocytized extracellular pathogen; peptide presented on MHC Class II molecule means HELP

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8
Q

What is the difference between CD8 and CD4?

A

Both T cells
CD8 = kill
CD4 = help

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9
Q

How does peptide bind to MHC I?

A

Usually peptides are 9 AA in length and oriented w/ NH2 terminus to the left
3, 5, and 7 are recognized by the TCR on the outside
2 and 9 AA are in MHC pockets that confers specificity for AAs with similar physical properties (size, charge, hydrophobicity, etc)
MHC can bind homologous peptides that can derive from different proteins that have P2 and P9 side chains composed of homologous AAs

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10
Q

How do T cells recognize an antigen?

A

TCR are capable of recognizing AA sequence ~9-16 AA long
TCR is bound to MHC molecules (aka HLA molecules)
TCR is specific for each antigen sequence
Both the amino acids of the bound peptide and the presenting MHC molecule are recognized by the TCR

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11
Q

How are T cells activated?

A

Dendritic cells are activated and migrate to lymph node where the naive T cells are waiting
There is a chance meeting b/w DC and helper T cell (immune synapse)
The effector T cell activates cytokines and CD40L

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12
Q

How does the cell surface flag a NK cell to signify trouble?

A

Foreign proteins in the cell membrane (viral envelop/mutated self)
Cell surface distress proteins (MICA, MICB)
Loss of MHC I expression

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13
Q

What are CD8 cells?

A

Cytotoxic T Cells
Potent agents of cell death - activate target’s apoptotic program
Cause DNA fragmentation, blebbing (which allows for easy phagocytosis)
Secrete cytokines (IFN-g (which activate macrophages) and TNF-a)

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14
Q

What does FasL do?

A

Engages target cell fas and initiates apoptosis
May be cleaved for secretion as well
FasL finds Fas complex, which links to FADD, initiates Caspase 8 to Caspase 3 to DNase/Lipase/Proetase

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15
Q

What does perforin do and where is it found?

A

Found as part of CD8 T cells

It’s homologous to C9; is a pore former (cytotoxic granule)

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16
Q

How does T cell bind to target?

A

Tight cellular adhesion

LFA-1 on T cell binds ICAM-1 on target

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17
Q

How are CTL made?

A

Naive CD8 T cells are precursors (no perforin, granzyme, or FasL)
High threshold for optimal activation
Collaborative effort involving licensing (of DC by a CD4 Th cell and of CD8 CTL by a licensed DC)

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18
Q

What are the 2 licensing models?

A
  1. Sequential (Th to APC; licensed APC to naive CD8 cell; licensed CTL)
  2. Simultaneous (Everything happens at once!)
    Once it’s licensed, CTL undergoes clonal expansion
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19
Q

How can a DC present the same pathogen to a CD4 Th cell and a CD8 CTL precursor?

A

Remember: CD8 w/ MHC I - intracellular Ag vs. CD4 w/ MHC II - endocytosed Ag
DC has cross-presentation - one cell can take endocytosed cells and leak them into cytoplasm to release to MHC I

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20
Q

How do viruses evade CD8 CTL?

A
  1. latency - minimize viral gene activation
  2. Antigenic variation - rapid mutation of viral genome
  3. Modulation of molecules involved in antigen presentation (interfere w/ antigen processing, loading, or MHC Class I expression)

Can also infect “immune privileged sites” or be resistant to apoptosis

21
Q

What affects a NK?

A

It’s the “accountant w/ a chainsaw”
Has inhibitory receptors (target gets a “credit”, can live another day)
OR excitatory receptors (target gets a “debit”, one step closer to apoptosis)

22
Q

What is KIR?

A

Killer Ig-Like Receptor as part of NK
Detects the presence of MHC on target - counts as a major “credit” for the target
Cytoplasmic tail contains “ITIMs” (immunotyrosine-based inhibitory motifs)
Phosphatase recruitment dampens signaling

23
Q

What is NKG2D?

A

Activating component of NK cells
Recognizes MICA and MICB, markers of cell stress (MHC homologs w/out peptide)
Provides an activating signal similar to CD28 on a T cell
Counts as a “debit” for the target

24
Q

What is Fc(gamma) Receptor III?

A

Part of NK Cell Excitatory Response
Binds IgG coating the target cell (viral env proteins, mutated tumor proteins)
ITAMs in cytoplasmic tail recruit kinases
Definite “debit” - favors NK activation (ADCC)

25
Q

What do TLR3 and TLR7 do?

A

Recognize viral RNA

Big debit for NK cell

26
Q

What is the CD56bright subset?

A

Subset of NK cells (10% in blood, majority of NKs in secondary lymphoid tissues)
Little to no killing capacity
Rapid and copious cytokines production (IFNg and TNFa)

27
Q

How do T cells recirculate?

A

T cells enter lymph node cortex from the blood via high endothelial venules (HEVs) - the vast majority are not activated by antigen and exit via the sinuses; twice daily they circulate b/w bloodstream and lymphatic system
If they are activated (1:10,000 to 1:100,000) by antigen, they start to proliferate and lose the ability to exit the lymph node

28
Q

What is the structure of the lymph node?

A

B cell zone w/ follicles/germinal centers on outside
T cell zone below w/ HEVs
Both are part of cortex (above the medulla)

29
Q

How do lymphocytes exit HEVs?

A

Via defined “Exit Ramps”
This is through the FRC Network
Up to 30,000 lymphocytes/sec in a single LN are exiting through HEV
B cells have the FDC (Follicular Dendritic Cell) Network

30
Q

How does MHC diversity arise?

A
  1. Duplication of a gene locus in an individual (polygeny) - ex HLA-A and HLA-B in the same person (isoforms)
  2. Development of multiple alleles at a locus among individuals in the species (polyallelism) - ex HLA-A01 vs HLA-A02, etc
31
Q

How many combos of MHC Is are there? IIs?

A

MHC I: 26 bil

MHC II: 1 tril

32
Q

Why do we have MHC polymorphism?

A

No practical biologic limit on the number of alleles for the species
Frequency-dependent selection (the individual w/ the rarest allele has the best chance to survive an epidemic)
Heterozygotee advantage - the individual with more MHC structures can present more different pathogen peptides

33
Q

How does duplication of an MHC locus incur a risk?

A

Each MHC type selects its own allele-specific TCR clonal repertoire capable of recognizing additional pathogen peptides;
Each duplication increases the size of immune self and mandates more negative clonal selection across all repertories during each repertoire formation, reducing the size of the TCR repertoire for each allele

34
Q

How many loci are there for each class?

A

3
Class I: HLA-A, HLA-B, HLA-C
Class II: HLA-DR, HLA-DQ, HLA-DP
There are both maternal and paternal alleles, so there are 6 different class I alleles

35
Q

Define: Allelotype (or allelomorph)

A

Different or alternative protein forms encoded by alleles

36
Q

Define: Linkage disequilibrium

A

Certain alleles making up a haplo type are found together significantly more (or less) frequently than by chance
This allows for ancestral or extended haplotypes

37
Q

What does HLA-A*02:01 mean?

A

HLA-A (gene) - 2:01 (specific HLA protein)

38
Q

Define: Specificity (as it relates to HLA)

A

Allele group or family (eg HLA-B*27) to make things a bit easier
These were used to first detect HLA serologic specificities or antigens

39
Q

How do HLA genetics affect transplantation?

A

A graft is compatible only if there is a complete match at all MHC alleles (i.e. A two haplotype match for all MHC loci)
In situations where a transplant is required, especially in the case of bone marrow, the family is first typed to find 2 haplotype matches before unrelated individuals are searched

40
Q

How do HLA affect the adaptive immune system?

A

MHC Class I binds P2 and P9 AAs - the anchoring and peptide bindings pockets can vary based on MHC

Remember the HIV example (B27 had 15 peptides that recognized HIV, B35 had 0, B07 had 5)

41
Q

How are MHC I and MHC II loaded?

A

MHC I: peptides synthesized in the cytosol

MHC II: produced by lysosomal degradation of endocytosed organism

42
Q

What stabilizes MHC Class I?

A

Peptide
Beta2 microglobulin

Empty MHC Class I are unstable; stabilizing prevents “friendly fire” killing of bystander cells by the uptake of random peptides by empty MHC molecules

43
Q

What is the invariant chain?

A

A chaperone that complexes w/ MHC Class II during their synthesis in the ER
It blocks the peptide groove in the ER and prevents loading by peptides destined for Class I
A recognition sequence on the invariant chain transmembrane portion redirects the nascent MHC II molecule to traffic to the acidic endosomal compartment where it will be loaded w/ exogenous peptides

44
Q

What is CLIP?

A

Degraded Invariant Chain
Is still bound to the Class II molecule
HLA-DM then catalyzes the release of CLIP and the binding of high-affinity peptides
MHC Class II can now traffic the cell to the membrane

45
Q

What is unique about HLA-DRA?

A

There’s only 1 allele (they’re all the same - monomorphic)

46
Q

What are the max # of different HLA molecules that can be expressed on the cell surface?

A

Class I: 6
Class II: 10
MHC molecules are codominantly expressed
Class I molecules are found on the surface of all nucleated cells, class II are found on professional APCs

47
Q

How is the MHC complex composed?

A

2 sub unites - alpha subunit (linked to head domain w/ antigen-binding groove) and beta2microglobulin

48
Q

What is the TAP transporter?

A

Takes peptide fragment to ER to be bound to MHC Class I (which has a heavy chain that is membrane-bound in the ER)

Immunology (6 decks)

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