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Immunology > T cell receptors and MHC proteins > Flashcards

T cell receptors and MHC proteins Flashcards

1
Q

what are the types of T cell receptors?

A

T helper cells – CD4+ve: Augment immune responses

T cytotoxic cells – CD8+ve: Specifically kill infected host cells

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2
Q

how are TCRs expressed?

A

only on membranes, not as soluble proteins

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3
Q

what is the structure of TCRs?

A
  • C-terminus has hydrophobic amino acids to embed into the membrane
  • Alpha chain and beta chain linked by flexible disulphide bond hinge
  • Broadly Fab-like structure
  • Extracellular domains of the T cell receptor are homologous to the variable and constant regions of immunoglobulins.
  • Each V region contains 3 CDRs
    o Vα and Vβ domains each have 3 CDRs (1 – 3)
  • CDR3 regions of a and b chains are the most variable.
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4
Q

what are the two subsets of TCRs?

A

alpha-beta TCRs - 95%, more diverse

gamma-delta TCRs - 5%, less diverse

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5
Q

what does expression of TCRs on the cell surface require?

A

Expression of TCR on the cell surface requires association with additional proteins, called CD3

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6
Q

what is the TCR complex?

A

alpha and beta subunits, CD3 subunits (epsilon, delta, gamma) and zeta
- this complex is required for optimal cell surface expression and signalling

CD3 subunit associates closely with the alpha-beta chains of TCR

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7
Q

what is the CD3 subunit comprised of?

A

epsilon, delta, gamma subunits and zeta subunit

ITAMs in its cytoplasmic region which can be phosphorylated to lead to downstream signalling

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8
Q

what makes up the TCR genes?

A

2 gene loci, each for alpha and beta chains
- alpha: chromosome 14, made of 2 exons for V region and lots of J regions (like light chain)
- beta: chromosome 7, made of multiple V exons, J exons and D exons (like heavy chain)

these gene recombine in the thymus

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9
Q

how do TCR genes recombine?

A

Somatic recombination of TCR V region genes:
- Same recombination machinery as that used by developing B lymphocytes.
- Occurs in thymus
- J exon recombined to lie next to a V exon and then the C region
-Rag1 and Rag2 proteins facilitate this in the thymus

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10
Q

what processes drive TCR diversity?

A
  1. Multiple copies of V region gene segment [Vn x Jn/Vn x Dn x Jn]
  2. alpha x beta chain combination [Va x Ja] x [Vb x Db x Jb] = ~ 6 x 10^6
  3. Junctional diversity = ~2 x 10^11
    - Concentrated in the CDR3s of TCR alpha and beta chains

Total diversity = ~ 10^18
- Greater than B cell diversity as they have more gene segments than B cells

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11
Q

how are the CDRs encoded for in TCRs?

A

CDR1 and CDR2 encoded in germline, whereas CDR3 is generated via VDJ recombination

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12
Q

why do TCRs not undergo somatic hypermutation?

A

The V regions of TCRs do NOT undergo somatic mutation
- Possibly too dangerous – high likelihood of TCRs that recognise the body’s own tissues
- Doesn’t need to bind to antigen in free solution like antibody, so may not need to bind with such high affinity
- needs to still recognise MHC proteins to function - mutation may disrupt this

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13
Q

what are B cells important for? what kind of antigen do B cells recognise?

A

B cell immunity is particularly important in defence against extracellular pathogens
- B cells recognise free, native antigens on the surface of pathogens

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14
Q

what are T cells important for? what kind of antigen do T cells recognise?

A

T cells are important in defence against intracellular pathogens e.g. viral infections
- T cells recognise cell-associated, processed antigen

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15
Q

how do T cells recognise intracellular pathogens?

A

Major histocompatibility proteins (MHC):
- protein → peptide → MHC → cell surface → T cell recognition
- Protein is degraded into peptide, which is bound to MHC and transported to the cell surface for recognition
- T cells recognise cell-associated, processed antigen
- Samples of antigenic material inside the infected cell are displayed on the surface to be recognised by the T cell

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16
Q

what do T cells require to recognise antigen?

A

T cells require antigen presentation by cells expressing MHCs

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17
Q

what are MHC proteins?

A
  • Discovered during research on graft rejection.
  • Encoded by the genes of the Major Histocompatibility Complex Chromosome 6 (in humans)
  • Also known as HLA molecules in humans (human leukocyte antigen).
  • e.g. HLA-A, HLA-B, HLA-C – 3 gene loci encoding 3 different MHCs
  • very polymorphic
  • e.g. >1400 alleles of HLA-B locus. Alleles may differ by up to 20 a.a. substitutions
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18
Q

what is the major role of MHC proteins?

A
  • major role in antigen presentation and initiation of T cell responses
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19
Q

what is MHC restriction?

A

T lymphocytes can only recognise antigen in the context of self-MHC molecules

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20
Q

how was MHC restriction discovered?

A

Experiments with inbred mouse strains and virally infected cells
- Had the same MHC proteins on their surface
- Strains A and B were immunised with a virus and their T cells were isolated and cultured with cells infected with the same virus
- If T cells are taken from strain A and mixed them with cells from mouse A, then the T cells kill the infected cells
- If T cells are taken from strain B, the T cells were unable to kill infected cells from mouse A
- Cannot kill cells from a different strain
- T cells will only recognise antigen presented by self-MHC proteins

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21
Q

what were the two theories for MHC restriction?

A

2 receptors on T cells – one (TCR) for antigen, one for MHC?

1 receptor on T cells (TCR) – recognises antigen + MHC?

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22
Q

why does MHC restriction occur?

A

determined by x-ray crystallography:
- Saw unknown peptide antigen bound as part of the structure
- Proved that T cells recognised self-MHC associated with foreign peptide (antigen)

23
Q

what did crystallographic studies on TCR and MHC demonstrate?

A
  1. MHC binds peptide
  2. TCR recognises complex of foreign peptide + self-MHC
  3. CDR1 and CDR2 bind self-MHC (germline encoded, which is why T cells don’t undergo somatic mutation)
  4. CDR3 binds peptide - variation induced by junctional diversity
24
Q

what are the two types of T cells?

A

T helper cells - CD4+ve

Cytotoxic T cells - CD8+ve

25
Q

which MHC class interacts with CD8+ve cells?

A

MHC class I interacts with cytotoxic T cells
- Expressed by all nucleated cells
- Present peptides derived from endogenous proteins to cytotoxic CD8+ve T cells
- Endogenous – protein is synthesised by the infected cell

26
Q

which MHC class interacts with CD4+ve cells?

A

MHC class II interacts with helper T cells
- More restrictive expression pattern
- Expressed by certain leukocytes: dendritic cells, B cells, macrophages – antigen-presenting cells
- Present peptides derived from exogenous proteins to helper (CD4) T cells
- Exogenous – protein taken up from outside the cell

27
Q

what is the structure of MHCI protein?

A

2 chains: alpha chain and beta chain
- polymorphic transmembrane alpha chain
- invariant b2-microglobulin to provide stability
- polymorphisms are clustered in domains furthest from the membrane which bind to antigen

28
Q

what is the structure of MHCII protein?

A

2 polymorphic transmembrane alpha and beta chains
- Domains closest to membrane are immunoglobulin-like, and furthest are most polymorphic

29
Q

what are the functional domains of MHC proteins?

A
  • Membrane-proximal domains are Ig-like
  • Membrane-distal domains are bind peptide
  • Membrane distal domains contain polymorphism
30
Q

how do MHCI proteins bind peptide?

A

MHCI bind peptides 8-10 amino acids long:
- Bottom of groove made of beta-pleated sheets, and alpha-helices curl up the sides of the domain
- N and C-termini of peptides bind to invariant sites at ends of the groove.
- Two or three “anchor residues” on the peptides bind to “specificity pockets” formed by polymorphic residues at the base of the groove
- Fairly closed to restrict length of peptide that can bind

31
Q

how do MHCII proteins bind to peptide?

A

MHCII bind peptides 13-18 amino acids long:
- Peptide backbone interacts with conserved residues that line the base groove
- “Anchor residues” on the peptide bind to “specificity pockets” formed by polymorphic residues.

32
Q

what is a proteosome?

A

multi-subunit complex that breaks down misfolded proteins

33
Q

what is an immunoproteosome?

A

proteosome induced by interferon

34
Q

how does MHCI present antigen to CD8+ve cells?

A

e.g virus-infected cell presenting to cytotoxic T cell
-Cell that is infected with virus will convert the proteosome to an immunoproteasome to process peptide to the right length (8-10 aa) to interact with MHCI
- Peptides transported to ER by ATP-hydrolysis driven transporter, TAP (transporter associated with antigen presentation)
- Peptides loaded onto MHCI in ER
- MHCI-peptide transported to cell surface for recognition by cytotoxic T cell

35
Q

how does MHCII present antigen to CD4+ve cells?

A

e.g. macrophage/dendritic cell/B cell taken up antigen and needs help from T helper cell (CD4+ve)
- antigen taken up by phagocytosis or endocytosis
- phagolysosome breaks down the bacteria - acidification in vesicles promotes unfolding & proteolysis
- longer peptides (13-18 aa) associate with MHCII in the endocytic compartment
- MHCII-peptide transported to cell surface for recognition by helper T cell

36
Q

what is cross-presentation by MHCs?

A
  • Some dendritic cells present exogenous peptide associated with MHCI to cytotoxic T cells
  • Triggers naïve cytotoxic T cell to be active
  • Dendritic cell isn’t actually infected
  • Allows antigen presentation to cytotoxic T cells without the dendritic cells themselves being infected
  • Important in cytotoxic T cell responses to tumours
37
Q

what is required for T cell activation?

A

TCR complex (alpha-beta, CD3, zeta-chain), MHC and co-receptor

38
Q

what is the role of co-receptors on the T cell?

A

to stabilise the interaction between TCR and MHC to facilitate signalling

39
Q

what is the co-receptor of cytotoxic T cells?

A

CD8

40
Q

what is the co-receptor of T helper cells?

A

CD4

41
Q

which co-receptor does MHCII + antigen interact with?

A

CD4 co-receptor

42
Q

which co-receptor does MHCI + antigen interact with?

A

CD8 co-receptor

43
Q

how do T cell co-receptors function?

A

CD4/CD8 interact with invariant regions on MHCII/MHCI - not polymorphic

CD4 and CD8 act as co-receptors for the TCR complex. Both contain Ig-like domains

Engagement of the CD4/CD8 co-receptors with the TCR complex enhances phosphorylation of the ITAMs, promoting T cell activation
- CD4/CD8 C-terminus associates with Lck tyrosine kinase which phosphorylates ITAM motifs on the CD3 complex which is associated with the TCR

44
Q

what is thymic selection?

A

T cell enters thymus and undergoes somatic recombination of TCR genes
- Rearrangement of T cell receptor genes (αβ γδ)
- TCR must be able to recognise self-MHC but doesn’t react against self
- MHC selection (only in αβ chain T cells) (gamma-delta doesn’t require antigen presentation)

45
Q

what is positive MHC selection?

A

TCR must bind to self-MHC
- T cells which fail this undergo apoptosis

46
Q

what is negative MHC selection?

A

any TCRs which bind to self-peptide undergo apoptosis

46
Q

how are T cells exposed to non-thymus proteins during thymic selection?

A

AIRE allows expression of non-thymus proteins in the thymus
- e.g. insulin, so that the TCR doesn’t recognise self-proteins
- prevents autoimmune disease

47
Q

how are MHC proteins encoded?

A

Encodes by the Major Histocompatibility gene Complex (MHC), expressed on chromosome 6
- MHCI – 3 gene loci: HLA-A,B,C encode for polymorphic alpha chain
- MHCII: 3 gene loci: HLA-DP,DQ,DR encode for polymorphic alpha and beta chains
- very polymorphic e.g. HLA-B has 5000 alleles

48
Q

how are MHC proteins diverse?

A

Co-dominant expression (i.e. alleles inherited from each parent expressed on cells): increases no. MHC proteins on surface of cells to allow binding of a wide range of peptides
- however MHC diversity is inherited and small compared to that of B and T cell receptors

49
Q

which part of the MHC protein facilitates diversity?

A

Allelic variation occurs predominantly in the peptide-binding groove
- Diversity is in region of molecule that recognises antigen peptide

50
Q

what are the consequences of MHC polymorphism?

A
  • graft rejection
  • ensures wide recognition of foreign peptides BUT variability of MHC molecules is small compared to that of TCR (all inherited in genome)
  • T cell responses determined by an individual’s MHC type
  • each MHC allele can bind a restricted range of related peptides - Responders and Non-responders
  • e.g. Inbred mice have MHC proteins which don’t respond to antigens
  • MHC polymorphism evolved in response to pathogen - Black death? Flu? HIV?
51
Q

what are the functions of MHC proteins?

A
  • antigen presentation to T cells, T cell activation
  • development of T cell repertoire/tolerance in thymus
  • self/non-self-recognition (NK cells “detect” alterations MHCI)
  • when they detect self-MHC, NK cells are inhibited from killing
  • association with certain autoimmune diseases
  • Choice of mate? – attracted to someone with different MHC proteins from self
52
Q

summarise antigen presentation to T cells:

A
  1. CD8 and CD4 act as co-receptors for the TCR, interacting with MHCI and MHCII, respectively, and contribute to T cell activation.
  2. MHC proteins play a role in thymic selection
  3. MHC proteins are very polymorphic and co-dominantly expressed, allowing binding of a wide range of peptides
  4. An individual’s T cells can only recognise antigen presented by self-MHC molecules (MHC restriction).

Immunology (8 decks)

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