L7- T Cell Development and MHC Flashcards
1
Q
What is the main effector function of CD8 cytotoxic T cells?
A
Kill virus-infect cells
2
Q
What are the pathogens targeted by CD8 cytotoxic T cells?
A
- Viruses,
2. Some intracellular bacteria
3
Q
What is the main effector function of CD4 TH1 cells?
A
- Activate infected macrophages.
2. Provide help to activate naïve B cells for antibody production and induce class switching
4
Q
What are the pathogens targeted by CD4 TH1 cells?
A
- Microbes that persist in macrophage vesicles e.g. mycobacterium, Listeria, Leishmania donovani, Pneumocystis carinii
- Extracellular bacteria
5
Q
What are the main effector functions of CD4 TH2 cells?
A
Provide help to B cells for antibody production, especially for switching to IgE
6
Q
What are the pathogens targeted by CD4 TH2?
A
Helminth parasites
7
Q
What are the main effector functions of CD4 TH17?
A
- Enhance neutrophil response
2. Promote barrier integrity (skin, intestines)
8
Q
What are the pathogens targeted by CD4 TH17?
A
- Klebsiella pneumoniae
2. Fungi (Candida albicans)
9
Q
What is the main effector function of TFH cells?
A
B cell help isotope switching and antibody production
10
Q
What are the pathogens targeted by TFH cells?
A
All types
11
Q
What are the main effector functions of CD4 regulatory T cells (various types)?
A
Suppress T cell response
12
Q
Where is the thymus located?
A
Anterior mediastinum
13
Q
What is the main function of the thymus?
A
Site where T cells develop from committed non-functional precursors into mature T cells able to respond to all foreign antigens
14
Q
What do thymectomised mice reveal?
A
Dramatic decrease in circulating lymphocytes and a permanent loss of most T cell function
15
Q
Why can the thymus fail to develop?
A
- Humans with a congenital birth defect (DiGeorge’s syndrome)
- Nude mice
- Absence of circulating T cells, failure of cell-mediated immunity and an increase in infectious disease
16
Q
Immature progenitor cells in the thymus are called ….?
A
Thymocytes
17
Q
List the steps to T cell maturation
A
- T cell progenitor cells develop in the bone marrow and migrate to the thymus
- T-cell precursor rearranges in T cell receptor genes in the thymus
- Positive and negative selection in the thymus (immature T cells that recognise self MHC receive signals for survival. Those that interact strongly with self antigen are removed from the repertoire).
- Mature T cells migrate to the peripheral lymphoid organs where mature T cells encounter forge in antigens and are activated.
- Activated T cells proliferate and migrate to sites of infection and eliminate infection
18
Q
The earliest cells do not express CD4 or CD8 and are termed…..?
A
Double negative
19
Q
What types of thymocytes never express CD4 or CD8?
A
TCR composed of γ:δ chains (5-10%)
These are exported to peripheral blood
20
Q
Thymocytes with which TCR is most predominant?
A
α and β chains
21
Q
Thymocytes are also ‘positively’ selected for ability to recognize self MHC, and ‘negatively’ selected for ability to recognize self antigen/ tissues. What happens to the positive selection?
A
Continues to maturate from double positive thymocytes to now become;
Single-‐positive α:β CD4 or CD8 T cells are exported to the peripheral blood
22
Q
Define the positive selection process in the thymus
A
If the thymocytes TCR engages in a low affinity interaction with self MHC molecule on the thymus epithelial cell, it is rescued from programmed cell death and continues to maturation.
23
Q
Define lack of positive selection in the thymus.
A
If the thymocyte TCR does not engage in any interactions with peptide-MCH molecule complexes on thymocytes epithelial cells, it will die by a default pathway of programmed cell death.
24
Q
Define negative selection of the thymus.
A
If the thymocyte TCR binds peptide-MHC complexes on a thymocytes antigen-presenting cell with high affinity or avidity, it is induced to undergo apoptotic cell death.
25
B cells and antibodies are able to recognise antigen in their native form, how do T cells recognise antigen?
As short peptides bound to MHC molecules.
26
CD8 + Cytotoxic T lymphocytes (CTL) recognize target cells that display peptide fragments of non-self proteins bound to which MHC molecules at the cell surface
MHC class I
27
Which cells have MHC Class I molecules expressed in the body?
MHC Class I expressed on all nucleated cells, most highly expressed in haematopoietic cells
28
Cells with MHC I recognise what?
Peptides from intracellular pathogens, especially viruses, are recognized by CTL and result in the infected cell being killed by a process of apoptosis (programmed cell death)
29
Which type of T cells recognize peptides resulting from antigen degradation within intracellular vesicles, displayed on the cell surface in the context of MHC Class II molecules
CD4 +
30
How do you distinguish the different types of CD4 + from each other?
Define on the basis of the cytokines they secrete and on their effector function.
31
Describe the Fab fragment region of an antibody molecule.
| Fab: antigen-binding fragment that binds to antigens
Disulphide-linked heterodimer. Each chain contains one Ig C (constant) domain and one Ig V (variable) domain of each of the heavy and light chains.
32
Where is the Ag-binding site located on an antibody?
At the juxtaposition of the V domain.
33
The T cell receptor also has a disulphide-linked heterodimer – each chain contains an Ig C-‐like domain and an IgV-‐like domain. The TCR Ag-‐binding site is also at the juxtaposition of the V domains so what is different about TCR to Ig?
TCR are anchored to the cell membrane and are not produced in secreted form
(Ig shape like a Y) while TCR is only one of 3 parts of the Y)
34
Describe the antigen binding region fo the TCR
The antigen-‐binding region of the TCR is formed by the Vα and the Vβ domains
• In the V region of each TCR chain there are 3 hypervariable or complementarity determining regions (CDRs)
35
Which CDR is the primary antigen recognition domain?
CDR3
36
What does the CD3 complex do?
Sits next to TCR and signals to the cell that antigen has bound.
CD3 is the pan-‐T cell marker: all T cells express this molecule.
Mature T cells are CD3 + CD4 + or CD3 + CD8 +
37
Describe the T cell receptor antigen recognition domain (CDR3)
* T cell receptors concentrate diversity in the third hypervariable region
* The D and J genes contribute to the third hypervariable loop (CDR3)
* The CDR3 forms the centre of the antigen-‐binding site of the TCR and mainly contacts the unique peptide component within the MHC/ peptide complex
38
CD3 consists of protein complexes and is composed of 4 distinct chains. What are they and what do they do?
γ, δ, ε, and ζ
These chains associate with a molecule known as the T-cell receptor (TCR) and the homodimeric ζ-chain (zeta-chain) which contains immunoreceptor tyrosine-based activation motifs (ITAMS) to generate an activation signal in T lymphocytes.
39
The TCR, ζ-chain, and CD3 molecules together constitute the TCR complex with assistance from ITAMs. How is the signal generated to activate the T cell?
γ, δ, ε, and ζ
These chains associate with a molecule known as the T-cell receptor (TCR) and the homodimeric ζ-chain (zeta-chain) which contains immunoreceptor tyrosine-based activation motifs (ITAMS) to generate an activation signal in T lymphocytes.
* CD3 cytoplasmic chains also contain ITAMs
* ITAM Tyr residues are phosphorylated as a first step in T cell activation when the TCR contacts peptide/MHC
40
5-10% of T cell receptors have γδ chains. How are they different from the αβ TCR?
* Similar in shape to the αβ TCR
* Specialized to bind to certain ligands, including heat shock proteins and non-peptide ligands such as mycobacterial lipid antigens
* May not be restricted by Classical MHC Class I and Class II molecules
* May bind to free antigen and/or may bind to peptides presented by non-‐classical MHC
41
What are the 4 T cell receptor genes?
TCRA, TCRB, TCRG and TCRD
42
For αβ TCR:
TCRA recombination is what?
joining of Vα to Jα
43
For αβ TCR:
TCRB recombination is what?
joining of Vβ, Dβ, Jβ
44
When are discrete segments joined by somatic recombination?
During T cell development
45
How are functional α-‐ and β-‐chains generated?
The same way that complete Ig molecules are generated.
| flanked by spacer recombination signal sequences; recognized by same enzymes
46
Describe the TCRα locus.
* TCRα locus (chromosome 14) consists of 70-‐80 Vα
* 61 Jα gene segments
* Single C gene
47
Describe TCRβ locus.
TCRβ locus (chromosome 7) has 52 Vβ gene segments located distantly from 2 clusters each containing:
* 1 Dβ
* 6 or 7 Jβ
* Single C gene
48
How many T cells with unique TCRs are estimated to circulate in the human host?
>1 million mature naïve T cells
49
How do T cells recognise antigen?
They recognise antigen as peptides displayed by MHC molecules
50
What do MHC class I molecules recognise?
MHC Class 1 molecules present intrinsic or endogenous antigen – antigenic peptides from viruses or other intracellular pathogens – to CD8 + cytotoxic T cells
Note: Intrinsic/ Endogenous
51
What do MHC class II molecules recognise?
MHC Class II molecules present extrinsic or exogenous antigen –ingested from the immediate extracellular environment -to CD4 + helper T cells
Note: Extrinsic/ Exogenous
52
What cells express MHC class II molecules?
MHC Class II expressed by professional antigen presenting cells (macrophages, dendritic cells, B cells).
Can also be expressed by other cell types, for example on exposure to IFN-‐γ; also expressed by activated T cells in humans; expressed by microglia in brain
53
MHC class I region contains 3 principle principle loci. Which ones?
HLA-‐A, -‐B, and –C
54
MCH class II region contains 3 which loci?
HLA-‐DR, -‐DP, and –DQ
55
Which chromosome can you find human MHC locus?
Chromosome 6
56
What are some less classified HLA molecules and what do they do?
* HLA-‐E, HLA-‐F, HLA-‐G, HLA-‐H are class Ib genes
* Less polymorphic than A, B, and C locus gene products
* Various functions: eg. HLA-‐E and HLA-‐G gene products involved in recognition by NK cells
57
Why is it important for MHC genes to be highly polymorphic?
* Each MHC locus has many alleles – variant genes that occupy the same loci and encode variants of the MHC protein
* The expressed MHC molecule determines which peptide antigen the cell can bind and present for surveillance by CD4 and CD8 T cells
58
Explain how zMHC alleles are codominant
MHC genes (a group or haplotype) are inherited from each parent
Alleles are expressed from both MHC haplotypes
The products of all alleles are found on all expressing cells
Offspring siblings are likely to differ in their expressed MHC – this results in difficulty finding matched donors for tissue transplantation (excerpt twins)
Every person expresses at least 3 different transplantation Class I proteins and 3 or 4 MHC Class II
59
Allelic variation occurs at specific sites in MHC molecules. What part and why is it so important?
Variation arising from genetic polymorphism is usually in the peptide-binding clefts.
Such variation can alter the specificity of an MHC molecule for a peptide antigen.
60
Explain the MHC class I structure
MHC-‐encoded HLA-‐A, -‐B, -‐C heavy chain α bound to β2 -microglobulin
* The α chain folds into 3 domains: α1 , α 2, and α 3. The α1 and α 2 domains form the antigen-‐binding groove
* Peptides (8-‐10 aa long) are stabilized at both ends of the groove by binding to invariant sites
61
MHC class I recognise peptides how many amino acids long?
8-10 aa long
62
Explain MHC class II structure
* Class II molecules -‐ HLA-‐DP, -DQ, -‐DR in humans -‐ are heterodimers of α and β chains
* No β2 -‐microglobulin
* Peptides are at least 13 aa long
* Ends are not bound to groove; peptide is held in place by interactions along its length
63
MHC class II recognise peptides how many amino acids long?
At least 13 aa long
64
Characteristic motifs distinguish peptides which bind to different MHC molecules. Why is this important?
MHC molecules therefore bind peptide antigens with amino acid sequences that comply with the MHC binding requirements
This means that a particular microbial protein can be scanned to check for amino acid sequences which ‘fit’ a particular MHC molecule
65
Explain the characteristic motifs that distinguish peptides which bind to Class I and Class II MHC
Class I MHC molecules typically have 6 pockets in the peptide-‐binding groove, with side chains from the peptide anchor residues extending to fill the pockets;
MHC Class II molecules have similar peptide binding specificities
66
T cell recognition of antigens is MHC restricted. What is meant by this?
* The TCR recognizes a complex of self-‐MHC and an antigenic peptide
* A T cell specific for peptide x and a particular MHC molecule A will not recognize the complex of peptide x with a different MHC molecule, or a different peptide y in the context of MHC A
67
CD4 and CD8 molecules bind to invariant sites on the MHC molecule on T cells. What role do they actually play?
This binding is required for the T cell to make an effective response and helps to stabilise interactions of TCR and MHC/peptide.
Also helps to facilitate the recruitment of a kinase to the TCR-MHC complex that is essential for initiating signalling.
68
Where do the CD4 and CD8 associate on MHC and T cell receptor?
CD4 and CD8 bind to the membrane-proximal domains of the MHC Class I and II molecules and leave the upper surface of the MHC molecule exposed and free to interact with a T cell receptor
69
Superantigens are molecules produced by many different pathogens, including bacteria, viruses, and mycoplasmas. Provide an example.
Examples are toxic shock syndrome toxin-‐1; staphylococcal enterotoxin B
70
Explain the superantigen recognition process.
They are recognized by T cells without being processed into peptides and presented by MHC
* Bind to the outside surface of MHC Class II
* Stimulation by a superantigen causes the CD4 + T cell to release very large amounts of cytokine
71
What is immunodominance?
* Protein antigens are processed to generate multiple peptides
* Immunodominant peptides are those that bind best to the available MHC Class I and II molecules
* The immunogenicity of foreign protein antigens depends on the ability of antigen-‐processing pathways to generate peptides from those proteins that bind to self MHC, and the presence of antigen‐specific T cells
72
What is meant by heterologous immunity?
Refers to the immunity that can develop to one pathogen after a host has had exposure to non-identical pathogens. It is relatively common within closely related species but can also be seen with unrelated species.
This can be protective or pathogenic.
