Iahi: 01 - Antigen Presentation And Receptor Diversity

Front 1

Can a Class II MHC molecule present self-peptides?

Back 1

Yes

Front 2

Where might the self-peptides that can be presented on Class II MHC molecules originate?

Back 2

- From proteins / cellular debris engulfed by phagocytic cells
- From proteins in lumen of lysosome

Front 3

How many gene products can our genome encode? Why is this problematic for the immune system?

Back 3

- ~25,000 gene products
- Need to be able to recognize millions of different antigens that we encounter on virtually any pathogen by generating antigen receptors for them

Front 4

Class I MHC molecules present peptides from where?

Back 4

Cytosol - degraded by proteasome

Front 5

What do T cell receptors (TCRs) recognize?

Back 5

Combination of self MHC molecule and peptide

Front 6

What are the three possibilities for the affinity between the T cell receptor (TCR) and the MHC molecule / peptide complex during develpment?

Back 6

- No affinity = T cell 1 (doesn't bind MHC or peptide)
- High affinity = T cell 2 (binds both MHC and peptide)
- Weak/Moderate affinity = T cell 3 and 4 (binds only MHC or only peptide)

Front 7

What are the implications of no affinity between the T cell receptor (TCR) and the MHC/peptide complex during development?

Back 7

T cell dies - death by neglect (#1)

Front 8

What are the implications of high affinity between the T cell receptor (TCR) and the MHC/peptide complex during development?

Back 8

T cell dies - too strong of a bond (#2)

Front 9

What are the implications of weak/moderate affinity between the T cell receptor (TCR) and the MHC/peptide complex during development?

Back 9

T cell lives to leave the thymus and populate the periphery (#3 and 4)

Front 10

What is alloreactivity?

Back 10

- Reactivity of T cells (or B cells) to non-self (allogenic) MHC class I or II molecules (Green MHC from transplanted tissue - recognizes self peptide as non-self)
- Some of the remaining T cell receptors may bind strongly to NON-SELF MHC and SELF-PEPTIDES (*principle behind allotypic graft rejection*)

Front 11

What are sources of foreign peptides?

Back 11

Infections

Front 12

What are the sources of foreign MHC molecules?

Back 12

Transplanted tissue

Front 13

What are the implications of a high affinity interaction in the periphery?

Back 13

Killing of target cell

Front 14

How does a T cell know whether it is seeing self or foreign peptide?

Back 14

- During development, we generate a population of newborn T cells that have the capacity to recognize everything, including self-peptide + MHC
- Then we eliminiate the T cells that recognize self-peptide + self-MHC
- Therefore, your remaining T cells would never form a high affinity bond with the self-peptide + self-MHC because they were eliminated!
- Only can form high affinity bonds w/ foreign peptides + self-MHC

Front 15

What are the two types of T cells?

Back 15

- CD4+ T Helper Cells
- CD8+ T Cytotoxic Cells

Front 16

What kind of T cells recognize Class I MHC molecules?

Back 16

CD8+ T cytotoxic cells

Front 17

What kind of T cells recognize Class II MHC molecules?

Back 17

CD4+ T helper cells

Front 18

During a viral infection, what kind of T cells do you need? Why?

Back 18

- CD4+ T helper cells help kickstart the production of antibodies
- CD8+ T cytotoxic cells are the effector cells that kill virus-infected cells

Front 19

If you have never been exposed to a virus, what is absent during the first exposure?

Back 19

Virus-specific T cells are absent

Front 20

How long does it take to generate virus-specific T cells?

Back 20

3-7 days

Front 21

After an initial infection w/ a virus, what happens to the virus?

Back 21

- The virus is engulfed by phagocytic cells (dendritic cell) at the site of infection
- Phagocytic cells migrate to nearby lymphoid organ (lymph node) containing B and T cells
- Antigen presenting cells that have engulfed pathogen present it on class II MHC molecules, which activates CD4+ cells
- Via cross-presentation, class I MHC molecules can also present extracellular peptides, thus activating CD8+ cells
- Normally, class I MHC molecules present cytosolic peptides (and so unless the virus infected the cell, it would be unable to activate CD8+ cells)

Front 22

Lymph nodes capture antigen from what tissues?

Back 22

Epithelia and connective tissue

Front 23

The spleen captures what kind of antigens?

Back 23

Blood-borne antigens

Front 24

Class I MHC molecules usually present what kinds of peptides?

Back 24

Cytosolic
(& extracellular via cross-presentation)

Front 25

Class II MHC molecules usually present what kinds of peptides?

Back 25

Extracellular

Front 26

On what kind of cells does cross-presentation happen? What does this mean?

Back 26

- Specialized antigen-presenting cells
- Class I MHC molecules can also present extracellular peptides (in addition to cytosolic)

Front 27

How can extracellular peptides access Class I MHC molecules?

Back 27

- Viral peptides somehow get into the cytosol
- It is unclear how this happens!

Front 28

What neutralizes extracellular virus particles?

Back 28

Antibodies made by B cells

Front 29

What are the insufficiencies of antibodies from B cells?

Back 29

- They neutralize extracellular virus particles
- Unable to eliminate the source of the virus

Front 30

If you take antibodies (produced by B cells) specific to a virus and transfer them to a non-infected mouse and then infect the mouse w/ the virus, what will happen?

Back 30

The mouse will be protected from the virus - passive immunity

Front 31

What is passive immunity?

Back 31

Transfer of active humoral immunity (antibodies from B cells) from one individual to another

Front 32

Under what circumstances is the idea of "passive immunity" utilized as a treatment?

Back 32

- Gamma-globulin (IgG) injection for HIV patients
- Hepatitis B antibodies to prevent infection even after exposure
- This is expensive because the half-life is ~30 days!

Front 33

If you take T cells specific to a virus and transfer them to a non-infected mouse (genetically identical) and then infect the mouse w/ the virus, what will happen?

Back 33

- Yes because genetically identical
- T cells will divide, don't have to worry about half-life

Front 34

If you take T cells specific to a virus and transfer them to a non-infected mouse (not genetically identical) and then infect the mouse w/ the virus, what will happen?

Back 34

- Not protected
- T cells always recognize foreign antigen in the context of self
- New strain of mouse has different "non-self" MHC molecules presenting the antigen which won't bind to the transferred T cells

Front 35

What is "MHC restriction"? How does it apply to the transfer of T cells between genetically different mice?

Back 35

- T cell receptors are specific for a type of virus antigen
- But they are restricted by self-MHC, so they don't protect a mouse with different genes

Front 36

What happens when you transplant tumors from one strain of mice into the same inbred strain (syngeneic/same genes) mice?

Back 36

Tumors fluorished and killed these mice

Front 37

What happens when you transplant tumors from one strain of mice into a different strain (allogeneic) mice?

Back 37

Tumors were quickly rejected w/in 2 weeks post transplant

Front 38

What did the studies of transplanting tumors into genetically similar (syngeneic) and dissimilar (allogeneic) mice tell us about tissue rejection?

Back 38

- Genetically heritable trait
- Genetic locus responsible for tissue rejection = Major Histocompatibility Complex

Front 39

What is the Major Histocompatibility Complex genetic locus?

Back 39

- The area on chromosome 6 that is responsible for tissue rejection
- Over 200 genes, spans ~7 million bp
- Contains class I and class II genes

Front 40

Are tumor rejection genes dominant/recessive/codominant?

Back 40

Codominant - A and B are both dominant alleles

Front 41

If you are AB for tumor rejection genes, what kind of tumors will not be rejected?

Back 41

A/A or B/B because you express both A and B

Front 42

What genes on the Human MHC locus of chromosome 6 are important for Class I molecules?

Back 42

HLA-A, -B, -C ("heavy chains")
(HLA = Human Leukocyte Antigen)
*Beta-2-m is not encoded on MHC gene locus*

Front 43

What genes on the Human MHC locus of chromosome 6 are important for Class II molecules?

Back 43

HLA-DR, -DQ, -DP (heterodimers - alpha/beta chains)
(HLA = Human Leukocyte Antigen)
HLA-DM and TAP
*Note that alpha and beta chains are encoded by different genes*

Front 44

What is the function of the HLA-DM gene?

Back 44

Bumps Invariant Chain (Ii) out of the binding site of Class II molecules

Front 45

What are the most polymorphic (many alleles at each locus within the population) genes in the genome?

Back 45

MHC class I and class II genes on MHC locus (chr 6)

Front 46

What characteristics about MHC molecules lead to such diverse recognition of foreign antigens?

Back 46

- Polygenic - 3 genes for Class I
- Codominant - gene product from mother and father are equally expressed (6 Class I molecules)
- Polymorphic - multiple alleles at each locus within the population

Front 47

What molecules are responsible for transplant rejection?

Back 47

MHC Class I and Class II molecules

Front 48

What are the odds that a sibling will match for all 10 products (assuming no recombination between loci)?

Back 48

1:4

Front 49

What are the 10 products that need to match for someone to be a good bone marrow donor?

Back 49

HLA-A, -B, -C x2 (class I)
HLA-DQ, -DR x2 (class II)
(HLA-DP isn't involved in transplant rejection)

Front 50

On what types of cells are Class I MHC molecules expressed?

Back 50

All nucleated cells

Front 51

On what type of cells are Class II MHC molecules expressed?

Back 51

Only on specialized antigen-presenting cells

Front 52

Which of the gene products of MHC Class II molecules is the most polymorphic?

Back 52

HLA-DR beta

Front 53

What does the T cell receptor recognize?

Back 53

Combination of both peptide and class I/II helices

Front 54

What are the common sites of polymorphisms/mutations on Class I MHC molecules?

Back 54

- Peptide-binding cleft
- On alpha helices and beta sheets of bed of heavy chain

Front 55

What are the common sites of polymorphisms/mutations on Class II MHC molecules?

Back 55

- Peptide-binding cleft
- On alpha helices and beta sheets of bed of beta chain

Front 56

What do the polymorphisms on the bed of the peptide-binding cleft affect?

Back 56

Which peptides can bind within this groove

Front 57

How can 6 distinct class I molecules and 6 distinct class II molecules be sufficient to handle all viruses and infections?

Back 57

- Range of sizes (8-10 resis for class I; 12-16 resis for class II, but up to 30+)
- Structural similarities of residues (e.g. peptide backbone, N-term, C-term)
- Each class 1 molecule can bind >1000 peptides, and each type binds unique sets

Front 58

How many distinct peptides can bind to each class I MHC molecule?

Back 58

>1000

Front 59

What constraints are there on the amino acid residues of the peptides that bind to MHC molecules?

Back 59

- Certain AA residues are anchor residues (blue)
- The rest can vary

Front 60

Which peptides (class I vs class II) are anchored at the ends?

Back 60

Class I peptides are anchored

Front 61

How many copies of each Class I molecule are there?

Back 61

10^5 (100,000) copies of each

Front 62

Why are cheetahs highly susceptible as a population to certain pathogens?

Back 62

They do not have polymorphic MHC alleles

Front 63

What percentage of people do not respond to the Hepatitis B vaccine? Why?

Back 63

- 5-15%
- They are homozygous for HLA-DR3 and -DR7
- Maybe these don't present the antigens for Hep B very well

Front 64

What is Ankylosing Spondylitis? What gene is common to it?

Back 64

- Inflammatory, possibly autoimune disease of vertebral joints
- HLA-B27 is found in 6% of the population, but approximately 93% of individuals w/ AS have HLA-B27

Front 65

How does the gene HLA-B27 predisopse people to Ankylosing Spondylitis?

Back 65

Having tissue type does not mean an individual will have AS, but it increases the chances of having AS by ~100-fold (it is currently being studied what the activating agent may be that triggers AS)

Front 66

What is the basic structure of a B cell receptor (BCR)?

Back 66

- Shape of a Y - membrane Ig (immunoglobulin) - integral membrane receptor
- Signal is transmitted through cytoplasmic tails of two associated proteins, Ig-alpha and and Ig-beta

Front 67

What is the basic structure of a T cell receptor (TCR)?

Back 67

- TCR is embedded in membrane with area for antigen binding
- Associates with several CD3 Dimers (together called the TCR complex)
- Signaling is transmitted through CD3 chains

Front 68

How many classes of antibodies (isotypes) are there? Names?

Back 68

5: IgM, IgD, IgE, IgA, IgG

Front 69

How do the five different classes of antibodies differ structurally?

Back 69

- Differ within their heavy chain (blue or read) constant regions (Fc)
- Light chains (green) are either kappa or lambda)

Front 70

How many molecules assemble to form an antibody?

Back 70

- 2 heavy chains (blue and red)
- 2 light chains (green)

Front 71

What structural components of the antibody should we know?

Back 71

- CH# = # constant region of heavy chain (CH1 found in Fab and CH2/3 found in Fc region)
- VL/H = Variable region of Light/Heavy chain, parts that contact the antibody
- Fc Region - base or tail of Y, only made of heavy chains
- Fab Region - limbs of Y, made of heavy and light chains - business end

Front 72

What are B cell receptors in their secreted, soluble form called?

Back 72

Immunoglobulins (Ig) or antibodies

Front 73

What components of an antibody form the business end?

Back 73

Fab region = CH1 and VL/H and CL

Front 74

Name letters A, B, C?

Back 74

A = VL (variable region of light chain)
B = CL (constant region of light chain)
C = VH (variable region of heavy chain)

Front 75

Name letters, D, E, F?

Back 75

D = CH1 (constant region 1 of heavy chain)
E = CH2 (constant region 2 of heavy chain)
F = CH3 (constant region 3 of heavy chain)

Front 76

Name letters A, B, C?

Back 76

A = VL (variable region of light chain)
B = CL (constant region of light chain)
C = VH (variable region of heavy chain)

Front 77

Name letters, D, E, F?

Back 77

D = CH1 (constant region 1 of heavy chain)
E = CH2 (constant region 2 of heavy chain)
F = CH3 (constant region 3 of heavy chain)

Front 78

What is the name of the structure boxed in yellow? Orange?

Back 78

Yellow - Fab region
Orange - Fc region

Front 79

What are the CDRs on an antigen?

Back 79

The portions of the antibody that contact the antigen; these are the portions that vary

Front 80

How many CDRs are there on an antigen? Where are they located?

Back 80

- 3 for the heavy chain variable region (VH)
- 3 for the light chain variable region (VL)
- CDR = complementarity-determining regions

Front 81

How are IgA and IgM similar (and different from the other antibodies)?

Back 81

- They are not secreted as the typical Y-shaped antibody
- IgA is a dimer
- IgM is a pentamer

Front 82

What joins the IgA and IgM antibodies?

Back 82

J-chain joins the dimers or pentamers

Front 83

What is avidity? What increases the avidity of IgA and IgM?

Back 83

- Avidity = strength of multiple bond interactions
- Multimeric features of IgA (dimer) and IgM (pentamer) increases avidity

Front 84

What is the difference between affinity and avidity? Example?

Back 84

- Affinity - strength of a single bond
- Avidity - strength of multiple bonds
- IgM has a low affinity for its epitopes but 10 low-affinity interactions leads to a high avidity

Front 85

Which antibody isotypes are monomers with the classic Y shape?

Back 85

IgE and IgG and IgD

Front 86

What are Isotypes?

Back 86

Differences in heavy chains (IgG vs IgA vs IgE vs IgD vs IgM)

Front 87

What are allotypes?

Back 87

Differences in a single AA (there are a few polymorphic residues) on the same antibody

Front 88

What are Idiotypes?

Back 88

Differences that happen between two of the same type of antibody in the same person within the variable region

Front 89

What is the structure of the T cell antigen receptor?

Back 89

- Like MHC and Ig molecules, the TCR also contains Ig domains
- "Business end" which can recognize >10^11 distinct specificities is at the top (most membrane-distal region)
- 2 similar chains, α and β, which form heterodimer
- Each chain has a Variable and Constant region
- Most membrane-distal ends have the CDRs - hypervariable regions

Front 90

What do antibodies recognize?

Back 90

Anything - chemicals, proteins, phosphorylated proteins, carbohydrates

Front 91

How can the many proteins (billions) of differing specificities be synthesized without using a large percentage of our DNA to encode them?

Back 91

- Rearrangement of genomic gene segments where one of a large number of Variable gene segments rearranges to pair w/ a J-region segment
- Construct is spliced w/ a Constant region gene segment (immunoglobulin light chains and TCR α chains)
- Same process occurs with Ig heavy chains and TCR β chains w/ addition of D-region segment

Front 92

What are the gene segments that recombine during cellular differentiation and maturation on the Variable Region of the Heavy Chain of the TCRβ and Ig VH?

Back 92

V, D, and J

Front 93

What are the recombination events that take place on the variable region of the heavy chain of TCRβ and Ig VH?

Back 93

1. Recombination of Heavy chain D and J
2. Recombination of V (variable region) with DJ
3. After transcription, VDJ is spliced w/ a μ Constant region gene segment
4. Later after B cell matures it can be spliced with δ gene segments
5. Cell expresses IgM and IgD
6. Once B cell has seen antigen in lymphoid organ, class switching (recombination again) can occur
7. Heavy chain transcript (V(D)JC) is then expressed within the cell, and then at the cell surface w/ a surrogate light chain

Front 94

What are the gene segments that recombine during cellular differentiation and maturation on the Variable Region of the Light Chain of the TCRα and Ig VL?

Back 94

V and J
(**No D - diversity segment)

Front 95

Which loci contain the D segment? How many?

Back 95

Ig VH has n=23 D segments
TCRβ has n=2 D segments
TCRα does not have any D segments

Front 96

What are the recombination events that take place on the variable region of the heavy chain of TCRα and Ig VL?

Back 96

1. V and J recombine
2. VJ recombines with a C segment to form a transcript for the light chain
3. Translated and expressed in combination w/ Ig heavy chain (or TCR beta chain) to form intact BCR or TCR (expressed on cell surface)

Front 97

What enzymes are responsible for recombination of immunoglobulin and TCR molecules? Location of expression?

Back 97

- Recombination Activating Genes (RAG-1 and RAG-2)
- Expressed in lymphocytes only

Front 98

What are the functions of RAG-1 and Rag-2?

Back 98

- Work together
- Recognize recombination signal sequences (RSS)
- Induce double-stranded breakage of DNA

Front 99

Where are Recombination Signal Sequences (RSS) found? What recognizes them?

Back 99

Flank V and D sequences - recognized by RAG proteins, which induce double-stranded breaks in DNA

Front 100

Once DNA is cleaved by RAG-1 and RAG-2, what happens?

Back 100

- Recombination even
- Break is repaired by ubiquitously expressed DNA-repair enzymes
- Including: DNA-PK (Protein Kinase)

Front 101

What is the role of DNA-PK (Protein Kinase)?

Back 101

- DNA repair enzyme
- Phosphorylates an enzyme (Artemis) that opens up hairpins

Front 102

What are the two types of diversity that contribute to the diversity of antigen receptors?

Back 102

- Combinatorial Diversity - V(D)J Recombination
- Junctional Diversity - enzymes that alter the junctions between the gene segments

Front 103

What are the 3 enzymatic mechanisms by which the junctions between the gene segments are altered (to increase diversity of antigen receptors)?

Back 103

1. Breakage of hairpins to generate Palindromic sequences = "P-nucleotides"
2. Addition of Non-templated nucleotides to sites of V(D)J recombination, catalyzed by TdT, forms "N-regions"
3. Exonucleases remove nucleotides from V, D, and J gene segments at time of recombination

Front 104

How many possibilities are there for all of the Ig V(D)J combinations? TCR V(D)J combinations?

Back 104

Ig: ~10^6 (1 million)
TCR: ~3x10^6 (3 million)

Front 105

What is the total potential repertoire of Ig combinatorial + junctional diversity combinations? TCR?

Back 105

Ig: ~10^11
TCR: ~10^16

Front 106

What is the chain of events that occurs to create P-nucleotides (first step of generating junctional diversity)?

Back 106

1. Recombination Signal Sequences (RSS) on different V, D, or J sequences are recognized and brought together randomly
2. RAG complex (RAG-1 and RAG-2) generates double-stranded breaks
3. Hairpins form
4. Artemis:DNA-PK complex opens hairpins to generate Palindromic "P-nucleotides"

Front 107

What is the chain of events that occurs to add N-nucleotides (second step in generating junctional diversity)?

Back 107

1. N-nucleotide (non-templated nucleotide) addition by TdT to P-nucleotides
2. Weak pairing of strands

Front 108

What is the chain of events that occurs to complete junctional diversity?

Back 108

1. Unpaired nucleotides removed by exonucleases
2. Gaps filled in and ligated

Front 109

What is the "cost" of generating junctional diversity?

Back 109

- Because this is a random process of nucleotide addition/excision, only 1 in 3 receptors will be in-frame
- Other 2/3 of receptors will be out of frame (useless) antigen receptors
- Hopefully the other chromosome will have an in-frame receptor locus

Front 110

What are the mechanisms of generating antigen receptor diversity?

Back 110

1. Combinatorial (multiple gene segments; VDJ)
2. Junctional Diversity
3. Mix and Match Pairing of Light and Heavy Chains
4. Somatic Hypermutation (discussed in another lecture)

Front 111

What is meant by allelic exclusion?

Back 111

- Expression of heavy chain gene product of either the maternal or paternal chromosome, but not both
- Ensures clonal specificity - each B cell produces only a single, unique receptor

Front 112

What is clonal specificity?

Back 112

Each B cell produces only a single, unique receptor

Front 113

If the first heavy chain recombination event occurs on the maternal chromosome and is successful, what happens to the paternal chromosome?

Back 113

Heavy chain on paternal chromosome will not rearrange and the cell will express the maternal gene product only

Front 114

If the first heavy chain recombination event occurs on the maternal chromosome and is unsuccessful, what happens to the paternal chromosome?

Back 114

- Rearrangement of heavy chain on the paternal chromosome will occur
- If successful, paternal heavy chain will be expressed
- If unsuccessful, cell will die

Front 115

Does recombination begin on the maternal or paternal chromosome always?

Back 115

No - it's a random process and may begin on either maternal or paternal chromosome

Front 116

What is required for an immature B cell to recognize an antigen?

Back 116

Once it expresses a completed antigen receptor on its cell surface

Front 117

Are all of the B cell receptors on a given B cell identical?

Back 117

Yes!
- The BCR is the product of a chromosomal rearrangement
- Only one allele is expressed and the other is shut down (allelic exclusion)

Front 118

What types of antigens will a naive B cell encounter in the bone marrow?

Back 118

Self cells - largely bone marrow stromal cells

Front 119

What happens when a BCR recognizes an antigen in the bone marrow with high affinity? Why?

Back 119

- It is recognizing a self-antigen
- Leads to a signaling cascade that triggers apoptosis
- BUT: It can turn on its RAG recombinases to rearrange its other light chain and try again for a BCR that does not possess high affinity for self-antigens in bone marrow

Front 120

What happens to B cells during negative selection?

Back 120

BCRs that react tightly with antigen die through a process called "negative selection"

Front 121

What percent of B cells survive selection and exit the bone marrow? What happens to the remainder?

Back 121

Only 10%
(90% of B cells are negatively selected because of high affinity bonds to self antigens)

Front 122

What are the steps in maturation and selection of B lymphocytes?

Back 122

- Stem cell - contains germline DNA for Ig, no expression
- Progenitor-B - rearranges first heavy chain (VDJ)
- Pre-B - recombined H chain gene (VDJ) and assembles with surrogate light chain; this indicates that it was successful
- Immature B - recombined H chain gene and recombined light chain
- Mature B - alternative splicing to form δ mRNA; membrane IgM and IgD

Front 123

What happens to the progenitor B cell?

Back 123

- Recombination of D and J heavy chains, followed by V and D heavy chains
- If allele #1 is successful forms productive Pre-B cell w/ productive μ heavy chain (inhibits rearrangement of allele #2 and induces κ light chain rearrangement)
- If unsuccessful, try allele #2
- If allele #2 is also unsuccessful, leads to cell death

Front 124

What happens to the pre-B cells that have a productive μ heavy chain from either allele #1 or #2?

Back 124

- Vκ recombines with Jκ on allele #1
- If productive μ + κ chains inhibit rearrangement of κ allele #2 and λ rearrangement (forms immature B cell)
- If unproductive, Vκ recombines with Jκ on allele #2
- If productive μ + κ chains inhibit λ rearrangement (forms immature B cell)
- If unproductive, λ rearrangement

Front 125

What happens to a pre-B cell with unsuccessful recombination of the κ light chains on both alleles?

Back 125

- Recombination of Vλ with Jλ on allele #1
- If successful, μ + λ chains inhibit λ rearrangement of allele #2 (forms immature B cell)
- If unsuccessful, recombination of Vλ with Jλ on allele #2
- If allele #2 is successful, form immature-B cell (w/ μ + λ chains)
- If λ allele #2 is also unsuccessful --> cell death

Front 126

Which chain is recombined first in a B cell? Then?

Back 126

- Heavy chain
- Light chain (μ or λ)

Front 127

Why are the progenitor T "Pro-T" cells referred to as "double-negative"?

Back 127

They do not express the T cell co-receptors CD4 or CD8

Front 128

What do progenitor T cells first express? What happens to it?

Back 128

- Pre-TCR - analogous to surrogate light chain that assebles with the first rearranged BCR μ heavy chain
- Can pair with a rearranged TCRβ when first expressed

Front 129

What happens to a progenitor T cell if a productively rearranged TCRβ is not expressed?

Back 129

Cell dies

Front 130

What signals are released from the pre-TCR/TCRβ complex? What do they signal?

Back 130

Cell survival signals - signal for TCRα gene recombination and inhibits further recombination at TCRβ locus (allelic exclusion)

Front 131

What happens if there is a failure to express a productively rearranged TCRα/TCRβ complex?

Back 131

Cell death

Front 132

T cells that survive (have productively rearranged TCRα/TCRβ complex) will express what? What are they called?

Back 132

T cell coreceptors CD4 and CD8 = Double-Positive Immature T cells

Front 133

What leads to the proliferation and expansion of immature T and B cell progenitors?

Back 133

Cytokine IL-7

Front 134

Where is cytokine IL-7 produced? Purpose?

Back 134

- Thymus for T cells
- Bone marrow for B cells
- Causes proliferation/expansion of immature T or B cell progenitors

Front 135

Do all of the T cell receptors on a given T cell have identical specificities?

Back 135

Yes

Front 136

What types of antigens will the T cell encounter in the thymus?

Back 136

Only self - thymic epithelial cells and other T cells
*But thymic epithelial cells express a transcription factor called "Aire"*

Front 137

What is the significance of the transcription factor "Aire" (autioimmune regulator)?

Back 137

- Turns on expression of many genes that are expressed elsewhere in the body - urinary tract, kidney, pancreas, Paneth cells, etc.
- Mainly turns on expression of tissue-specific genes, note genes that are expressed in every cell
- This allows the T cells in the thymus to recognize additional self peptides and destroy those T cells that bind tightly to self

Front 138

What kind of double-positive immature T cells survive in the thymus?

Back 138

Those that have "positive selection" - weak recognition of class II MHC + peptide or class I MHC + peptide

Front 139

What kind of double-positive immature T cells do not survive in the thymus?

Back 139

- Those that fail to undergo positive selection (death by neglect) caused by no recognition of MHC + peptide
- Those that undergo negative selection due to a strong recognition of Class I or Class I MHC + peptide

Front 140

How is immature T cell selection different from B cell selection?

Back 140

T cells must recognize peptides in the context of MHC molecules (self MHC molecules)

Front 141

What is the "T cell repertoire"?

Back 141

- Total number of antigen specificities exhibited in a single individual as determined by antigen-specific T cell receptors
- Each T cell displays receptors of a single specificity

Front 142

An inactivating mutation in which gene(s) could be responsible for a patient having essentially undetectable T cells or B cells, but normal numbers of NK cells?

Back 142

- RAG-1 or RAG-2 - expressed only in T and B cells; recognizes the RSS and generates double stranded DNA breaks; leads to absence or deficiency of T and B cells and Ig
- Artemis - failure to resolve hairpins during V(D)J recombination; leads to reduced Ig and absence or deficieny of T and B cells
- DNA-PK - identical to Artemis (works w/ Artemis to resolve hairpins)

Front 143

What are the implications of an inactivating mutation in RAG-1 or RAG-2?

Back 143

- SCID: Severe Combined Immunodeficiency - both B and T cell deficient, reduced serum Ig ("Bubble Boy Syndrome")
- Omenn Syndrome: RAG deficiency can be "leaky" and result in low rather than absent B and T cells - these patients develop a combination of immunodeficiency and autoimmunity

Front 144

What are the implications of an inactivating mutation in Artemis?

Back 144

- SCID: Severe Combined Immunodeficiency - absence or deficiency of T and B cells and reduced serum Ig
- Caused by failure to resolve hairpins during V(D)J recombination
*Identical to mutation of DNA-PK because they work together*

Front 145

What are the implications of an inactivating mutation in TdT?

Back 145

- Adds completely new non-template nucleotides after breaks have been made but before they have been repaired
- Without this there would be a less diverse repertoire of B and T cell receptors (only have combinatorial diversity ~10^6)

Front 146

What are the implications of an inactivating mutation in DNA-PK?

Back 146

- SCID: Severe Combined Immunodeficiency - absence or deficiency of T and B cells and reduced serum Ig
- Caused by failure to resolve hairpins during V(D)J recombination
*Identical to mutation of Artemis because they work together*