TCR and MHC

Question 1

MHC-restricted Antigen Recognition

Answer 1

T cell recognition requires TCR to recognize both:

1) self-MHC
2) peptide antigen

T cells are unable to recognize native or free antigens.

Question 2

T Cell

Receptor Complex

Answer 2

• TCR are disulfide-linked heterodimers
  
  • αβ (alpha/beta chains)
    
    • most common TCR type
  • γδ (gamma/delta chains)
    
    • first TCR made during embryonic development
    • minority, found predominantly at mucosal sites
• TCR non-convalently linked to CD3 and ζ-proteins (zeta)
  
  • Variable region of αβ subunits contact MHC and Ag complex
  • CD3 and ζ-chains transmit the signal into the cell
    
    • T-cells can be identified by CD3 expression

Question 3

TCR

Structure and Genes

Answer 3

• TCR polypeptides consists of two major domains:
  
  1. constant region
  2. variable region
     
     • Interacts with Ag/MHC
     • Composed of multiple gene segments assembled through gene rearrangement
     • α (and γ): V and J gene segments
       
       • Similar to BCR light chain
     • β (and δ): V, D, and J gene segments
       
       • Similar to BCR heavy chain
     • Joining region between the alpha and beta chains is where Ag binds

Question 4

TCR

Rearrangement

Answer 4

• Gene rearrangement occurs in the absence of Ag
• Events are random
• Allelic exclusion prevents both loci or two different TCRs from being expressed in a cell
• Utilizes similar components as BCR rearragement:
  
  • V(D)J recombinase
  • Exonucelases
  • TdT
• T-cells do not undergo somatic mutation after activation

Question 5

TCR

Mechanisms of Diversity

Answer 5

1. Multiple V, D, and J segments
2. Combinatorial diversity
   
   • V, (D), and J gene segment combinations
   • α and β chain combinations
3. Diversity gene segments (D) code in all three reading frames
4. Junctional diversity
   
   • Exonucleases
   • TdT

T cells do not undergo:

• Somatic mutation
• Isotype switching
• Affinity maturation

Question 6

HLA Locus

Answer 6

HLA (Human Leukocyte Antigens) locus composed of many linked genes on chromosome 6.

One of the most gene dense regions with > 100 genes.

Usually inherited as a group = haplotype.

Question 7

Class I MHC

Genes

Answer 7

• Encoded by HLA-A, HLA-B, and HLA-C genes
• Expresssed on almost all nucleated cells
  
  • Absent or minimal on:
    
    • brain
    • sperm
    • placental trophoblasts
    • early embryos
• Expression upregulated by:
  
  • Type I IFN’s (IFN-α and IFN-β)

Question 8

Class II MHC

Genes

Answer 8

• Encoded by HLA-DR, HLA-DP, HLA-DQ
• Expressed on:
  
  • Professional antigen presenting cells
    
    • Mature B cells
    • Activated macrophages
    • Dendritic cells
• Inducible on activated macrophages, some activated epithelial/endothelial cells, and others
• Expression upregluated by type 2 IFN (IFN-γ)

Question 9

Class III MHC

Answer 9

• Are NOT antigen presenting complexes
• Encode several secreted proteins associated with immune response
  
  • complement
  • TNF

Question 10

MHC Alleles

Answer 10

• MHC loci are highly polymorphic
  
  • In the hopes that some individuals within a population has MHC able to recognize all pathogens
• HLA alleles are codominantly expressed
  
  • One from each parent
• A single cell expresses multiple class I and II products on cell surface
• Generally inherited as a group called a haplotype
• 1/4 of siblings will share the same haplotype
• Strongly linked to autoimmune diseases

Question 11

Class I MHC

Structure

Answer 11

• Four immunoglobulin domains
• Each MHC polymer noncovalently attached to a β₂-microglobulin
  
  • β₂-microglobulin is not encoded by the MHC gene
  • More conserved
• CD8 on T-cell can bind to a conserved region of the molecule

Question 12

Class II MHC Structure

Answer 12

• Each MHC II composed of non-covalently linked α-chain and β-chain dimers
  
  • Forms four Ig domains
• CD4 can bind to a conserved region of the molecule

Question 13

MHC

Peptide-Binding Groove

Answer 13

• Both class I and II binding grooves formed by 8 anti-parallel β strands with two α-helical bridges
  
  • Like a hotdog (β strands) in a bun (α-helices)
• Groove binds short 8-18 AA chains (T-cell epitope) from the antigen
• Most MHC diversity exists in the groove
• MHC restriction of Ag recognition: when TCR engages it recognizes both the MHC’s α-helical bridges and the peptide lying in the groove
  
  • Epitope/MHC combination specific
  • Can require several different TCR’s to recognize the same epitope due to varrying MHC’s

Question 14

MHC

Promiscuous Binding

Answer 14

• Each individual has only 6 MHC genes which must present all necessary antigenic peptides to T-cell for activation.
• Peptide display is not as specific as the Ag recognition system used by TCR or BCR.
  
  • Allows each MHC molecule to present multiple peptides.
• Requirements for MHC binding:
  
  • Length
    
    • MHC I likes shorter peptides
    • MHC II likes longer peptides
  • Anchor residues
    
    • conserved peptide residues that secure the peptide into the peptide-binding groove
    • Usually 9 AA in length with specific AA at certain positions.