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3s2: Infection and Immunity > Week 3 > Flashcards

Week 3 Flashcards

1
Q

What cells lack class 1 MHCs?

A

Subsets of neurons and sperm cells at certain differentiation stages appear to lack class I
Red blood cells

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2
Q

What cell have MHC class II?

A

B cells, Macrophages and Dendritic cell (professional APCs)
Non immune cell being Thymic Epithelia due to needing to train T cells

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3
Q

What is an overview of MHC naming?

A

Human MHC is also called the HLA (human leukocyte antigen) complex
Mouse MHC is called the H-2 complex

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4
Q

What is an overview of class III MHC molecules?

A

Class III MHC molecules: group of unrelated proteins, no structural similarity or function with class I and II, although many do participate in aspects of immune response

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5
Q

What is an overview of MHC restriction?

A

T cells are self-MHC restricted, they recognized and respond to antigen presented by APC only if that APC expresses MHC molecules that T cells recognize as self.
It applies to both MHCI and II

If mice infected with strain A primed immune cells only respond to strain A not strain B and vice versa

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6
Q

What is an overview of the MHC-Class I structure?

A

Membrane bound glycoprotein
3 alpha chains and 1 Beta chain
Transmembrane domain
Cytoplasmic domain

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7
Q

What is an overview of alpha 1 and alpha 2 domain?

A

When folded for a 3d shape that generates the peptide binding domain for endogenously derived peptides

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8
Q

What is an overview of alpha 3 domain?

A

alpha 3: highly conserved sequence
Acts as a CD8 binding domain (where it will bind)

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9
Q

What is an overview of the Beta 2 microglobulin domain?

A

Associates with the apha chain which is regulated by Calreticulin, calnexin and ER57
Binds to Alpha chain in a non covalent manner
Lacks a transmembrane domain

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10
Q

What is an overview of MHC-Class I binding sites?

A

Antigen peptide = 8-10 amino acids, anchored at both ends
Specific amino acid residues near the N and C termini (generally hydrophobic (leucine or isoleucine) although charged residues have been seen)

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11
Q

What is an overview of MHC-Class II receptors?

A

2 alpha chains and 2 beta chains both memebrane bound

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12
Q

What constitutes peptide-binding domain on mhc II?

A

Formed from the binding of alpha 1 and beta 1 chain
No covalent bond joining them together

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13
Q

What constitutes MHC class II immunoglobulin like domain?

A

Formed from alpha 2 and beta 2
Beta 2 acts as the CD4 binding domain co-receptor

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14
Q

What is an overview of MHC-Class II binding sites?

A

Binding cleft, or pocket, is more open than class I
Antigen peptide 13-18 (or longer) amino acids; central core of 13 aa, with ends often ‘sticking up’
No specific requirements for particular amino acids, although aromatic and hydrophobic aa in parts of the core sequence
Assembly: roles for HLADM, li and CLIP

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15
Q

What is an overview of the binding of MHCs eg speed?

A

Very slow “on rate” and “off rate” unusually stable complexes Kd range from ~10-6 to 10-10
Each class binds one peptide at a time
Different (but similar) peptides can bind to the same MHC molecule
Some evidence for ‘peptide-splicing’

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16
Q

What are the characteristics of peptide-MHC binding?

A

Specificity - anchor residues
Peptide binding by a given MHC protein is selective but less specific than antigen binding by TCR or BCR

Flexibility - a series of antigenic peptides with the same consensus binding motif can be presented by a given MHC molecule

Which MHC alleles are inherited will determine which peptides can be displayed/presented

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17
Q

What is an overview of MHC genes?

A

Human MHC locus on chromosome 6 is over 4 million base pairs long and encodes over 200 genes
Each gene is highly polymorphic so in a population there is
considerable inter-individual variation
MHC proteins = highly immunogenic and therefore matching MHC prior to any tissue transplantation is extremely important

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18
Q

What is an overview of the number of MHC class 1 genes?

A

Class I MHC is a single a chain protein. Three different class I genes:
HLA-A, HLA-B and HLA-C all expressed on the cell surface

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19
Q

What is an overview of the number of MHC class 2 genes?

A

Class II MHC is a dimer of a and b chains each with 3 genes DR, DP and DQ

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20
Q

Why is the high polymorphism of MHC genes important?

A

Biologically the diversity at the MHC loci is valuable because the different genes and allelic variants can have different preferences for displayed peptides, thus diversifying the range of peptides recognisable by T cells

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21
Q

What is the impact of your MHC genes?

A

Particular set of MHC expressed by individual influences repertoire of antigens to which that an individual’s TH and TC cells can respond
Many alleles – which you inherit determines susceptibility to disease and development of autoimmunity

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22
Q

What are some of the known functions of MHC Class III genes?

A

Complement proteins: C4, Factor B, C2
Cytokines: LTB, TNF, LT

23
Q

What is unique about Beta 2 microglobulin

A

Beta 2 microglobulin encoded by gene outside the MHC locus

24
Q

What is an overview of MHC polymorphism?

A

Many alternative alleles (several 100 in total) exist at each locus amongst the population (up to 6 class I and 12 class II in any one individual). Rare for any 2 unrelated individuals to have same HLA genes. [Must be able to present enormous array of peptides]
Recombination frequency (cross-over) low; inherit one haplotype (set of alleles) from each parent

25
Q

What is an overview of MHC expression?

A

A single nucleated cell expresses ~105 copies of each of the unique class I molecules, each with different rules for peptide binding
Codominant expression (both maternal and paternal gene products expressed at same time in same cells)

26
Q

What is the difference between class 1 and class 2 expression?

A

The constitutive expression of Class I differs from that of Class II

27
Q

What is an overview of MHC transcription?

A

Rate of transcription is the major determinant of MHC expression (very little post-transcriptional regulation); some viruses very good at down regulation
Transcription of various Class I/II genes is well coordinated

28
Q

What is an overview of modulators of MHC transcription?

A

Cytokines are the key modulators of transcription of Class I/II genes: IFNs and TNF increase MHC I expression; IFN-g also increases class II

29
Q

What is an overview of T helper cells?

A

CD4
Recognises Ag with MHC II
Secretes cytokines (TH1 or TH2 response)
Activates B cells, TC cells, macrophages
MHC restricted

30
Q

What is an overview of cytotoxic T cells?

A

CD8
Recognises Ag with MHC I
Differentiates into Cytotoxic T lymphocyte (CTL)
Cell killing or cytotoxic activity
MHC restricted

31
Q

What is an overview of T cell receptors?

A

The receptor for peptide-MHC complexes on the majority
(90-99%) of T cells (CD4/CD8), is a heterodimer
consisting of two transmembrane polypeptide chains,
designated a and b, covalently linked by disulphide bonds

32
Q

What contributes to T cell recognition?

A

Both a and b chains contribute to the recognition specificity for the peptide-MHC complex
gamma delta receptors also occur – often in mucosal tissues; can recognise lipid or glycolipid moieties presented by non-canonical MHC molecules

33
Q

What is the B cell receptor?

A

Membrane bound IgM

34
Q

What is an overview of CD3 complex?

A

gamma delta epsilon - Essential for signalling
Positive charges in transmembrane domain of a and b chains
of TCR promote interaction with negative charges on chains
of the signal-transducing CD3 complex

35
Q

What is the relationship and similarities between CD4/ CD8?

A

Co-receptors
Mutually exclusive on mature T cells
CD4 binds to Class II, CD8 to Class I
Glycoprotein
CD4/8 promote the adhesion of MHC restricted T cells to APC
Participate in the early signal transduction events during T cell activation

36
Q

What are examples of molecules other than MHC required for stimulation of T cell?

A

Adhesion - ICAM-1/3 (APC) to LFA-1 (T cell)
Co stimualation - B7 (APC) to CD28 (T cell) (Naïve T cell requires co-stimulation of CD28)
Cytokine signals IL-1 to IL-1R and IL-2 to CD25

37
Q

What are the different outcomes for T cell activation?

A

MHC TCR binding but no co-stimulation = anergy
No MHC TCR binding but co-stimulation = no effect
MHC TCR binding, co-stimulation and cytokine = activation
Downregulation through B7 CTLA-4 binding

38
Q

What is the mechanism of T cell production?

A

Immature cells entering the thymus express no mature lymphocyte features and no antigen receptors
Double Positive (DP) CD4+ CD8+
Those leaving the thymus are naive but mature T cells diverse in receptor specificities and are both tolerant to self and restricted to self-MHC

39
Q

What are chemokines?

A

Chemokines produced by thymic stromal cells position developing T cells in the thymus

40
Q

What is the start of T cell maturation?

A

Precursors migrate into thymus through the vasculatures that are enriched around the cortico–medullary junction
Outward migration of CD4̶ CD8-DN thymocytes to capsule regulated by chemokine signals through CXCR4 and CCR7

41
Q

What happens to CD4-CD8-DN thymocytes during outward migration?

A

Further outward migration of DN (double negative) thymocytes to subcapsular region mediated by CCR9 signals
CD4+CD8 + DP (double positive) cells generated in outer cortex interact with stromal cells in cortex for positive/negative selection

42
Q

What happens after CD4+CD8 + DP cells are generated?

A

Surviving positively selected DP thymocytes differentiate into CD4 or CD8 SP thymocytes upregulate surface CCR7 for migration, which expresses CCR7 ligands

43
Q

What happens after positive selection and differentiation into CD4 or CD8 thymocytes?

A

In the medulla, deletion of tissue-specificantigen-reactive T cells and generation of regulatory T cells

44
Q

What happens to mature T cells?

A

Mature SP thymocytes express sphingosine-1- phosphate receptor 1 (S1P1), through which the cells are attracted back to the circulation that contains a high concentration of sphingosine-1- phosphate

45
Q

What is an overview of Central tolerance?

A

Selection of CD4+ and CD8+ single positive cells
Depending on specificity, Double Positive (DP) thymocytes
will downregulate either CD4 or CD8 to become single positive (SP) CD4+ or CD8+ thymocytes

46
Q

What mechanism guides downregulation to single postive?

A

The mechanism which regulates this is unknown, but is likely linked to the specificity of TCR for either class I or class II MHC molecules

47
Q

What is an overview of postive vs negative selection?

A

Thymic education involving positive and negative selection of T-cells ensures MHC restriction (positive selection) and T-cell reactivity against foreign but not self antigens (negative selection)
Vast majority (98%) of DP thymocytes do not meet selection criteria

48
Q

What happens with a lack of postive selection?

A

Apoptotic cell death by neglect

49
Q

What is an overview of positive selection?

A

Low affinity of peptide-MHC complex on thymic epithelial cells
Second round of low affinity antigen recognition
Those that fail are killed by apoptosis

50
Q

What is negative selection?

A

High affintiy interaction with thymic antigen presenting cells
If pass all three results in mature either CD4 or CD4 T cell

51
Q

What is an overview of Effector T helper cells?

A

Activates B cells that bind antigens (proliferation and differentiation so antibody production)
Activates macrophages that have engulfed antigens
Stimulates effector cytotoxic T cell that bind with antigen –> destroys infected host cell

52
Q

What are differnet Polarising cytokines and their type of T helper cell?

A

IL-12 = TH1 cell produces IFN gamma
IL-4 = TH2 cell produces IL4, IL-5 and IL-13
IL-6 = TH17 and TR1 produces IL-17A, IL-17F and IL-6 or IL-10
TGFBeta = TReg cell produces TGFBeta

53
Q

What different infections are the different type of T cells good against?

A

TH1 = Macrophage (intracellular bacteria and protozoa) and B cells (Extracellular bacteria)
TH2 = B cells (Extracellular bacteria) and Mast cells, Basophils and Eosoniphils (Helminths)
TH17 = B cells (Extracellular bacteria) and Neutrophil Fungi

54
Q
A

3s2: Infection and Immunity (12 decks)

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