Exam 1: TCR and MHC Flashcards

1
Q

MHC-restricted Antigen Recognition

A

T cell recognition requires TCR to recognize both:

1) self-MHC
2) peptide antigen

T cells are unable to recognize native or free antigens.

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2
Q

T Cell

Receptor Complex

A
  • 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
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3
Q

TCR

Structure and Genes

A
  • 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
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4
Q

TCR

Rearrangement

A
  • 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
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5
Q

TCR

Mechanisms of Diversity

A
  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
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6
Q

HLA Locus

A

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.

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7
Q

Class I MHC

Genes

A
  • 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)
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8
Q

Class II MHC

Genes

A
  • 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)
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9
Q

Class III MHC

A
  • Are NOT antigen presenting complexes
  • Encode several secreted proteins associated with immune response
    • complement
    • TNF
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10
Q

MHC Alleles

A
  • 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
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11
Q

Class I MHC

Structure

A
  • 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
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12
Q

Class II MHC Structure

A
  • 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
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13
Q

MHC

Peptide-Binding Groove

A
  • 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
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14
Q

MHC

Promiscuous Binding

A
  • 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.
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