9 - Development of T Cell Mediated Immunity Flashcards

1
Q

Where do T cells develop and mature

A
  • T cell precursors travel from the bone marrow to develop in the thymus
  • Mature T cells leave the thymus and travel to secondary lymphoid tissues
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2
Q

Secondary lymphoid tissues

A
  • Lymph nodes
  • Spleen
  • GALT
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3
Q

Types of cell in thymus (from cortex to medulla)

A
  • Cortical epithelial cell
  • Thymocyte (bone marrow origin)
  • Medullary epithelial cell
  • Dendritic cell (bone marrow origin)
  • Macrophage (bone marrow origin)
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4
Q

Two classes of TCR

A

αβ and γδ

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5
Q

What is stages in development of thymocytes marked by

A

Changes in cell surface molecules

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6
Q

Stages of development of thymocytes

A
  1. Double negative thymocytes (CD3-4-8-)
  2. Large active double postive (CD3+4+8+)
  3. Small resting double positive (CD3+4+8+)
  4. Small resting single positive (CD4+8- OR CD4-8+)
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7
Q

Recombination of TCR α

A
  • Coming together of 2 segments
  • Joining of Vα (Variable segement) to Jα (Joining segment)
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8
Q

Recombination of TCRβ

A
  • Coming together of 3 segments
  • Joining of Vβ (variable segment), Dβ (diversity segment), and Jβ (joining segment)
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9
Q

Recombination signal sequences (RSS)

A

Flank TCR gene segments

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10
Q

Which recombination in TCRs occurs first

A
  • Beta chain D-J recombination occurs first, followed by V-DJ recombination
  • Alpha chains do not have a diversity segment and thus recombination is limited to V-J
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11
Q

V(D)J recombinase

A
  • Recombination-activating genes RAG-1 and RAG-2 encode the RAG proteins that initiate V(D)J recombination
  • Complex is referred to as V(D)J recombinase
  • V(D)J recombinase introduces double-stranded breaks in germline DNA at the border between a RSS and a coding segmen
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12
Q

RSS

A

Recombination signal sequences that flank TCR gene fragments

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13
Q

Severe combined immune deficiency (SCID)

A
  • Occurs to do insufficient TCR diversity (recombination introduces diversity)
  • Absent or low T cells
  • Absent or non-functional B cells
  • High mortality in 1st year of life
  • Possible cure by bone marrow transplant
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14
Q

TCR V region rearrangement

A
  • Occurs by V(D)J recombination
  • RAG has endonuclease activity and makes single stranded cuts in the DNA between each coding
    segment and its RSS
  • This creates a 3’-OH group which then reacts with a phosphodiester bond on the opposite DNA strand to generate a hairpin, leaving a double stranded blunt end
    break
  • At the coding ends, the enzyme Artemis opens the hairpin
    and yields either two flush-ended DNA strands or a single strand extension
  • Cut end is then modified by enzyme terminal deoxynucleotidyl transferase (TdT) and exonuclease which randomly add or remove nucleotides
  • The two coding ends are ligated by DNA ligase IV
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15
Q

Which chain is arranged first

A
  • Functional β chain must be arranged first, before an ⍺ chain is generated
  • Each thymocyte has 4 attempts at making a functional β chain
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16
Q

4 attempts at making a functional β chain

A
  • 2 attempts on each allele
  • First try with Cβ1 fragment, then with Cβ2
17
Q

Pre T cell receptor (pre-TCR)

A
  • Consists of the TCRβ chain and the pre-TCR alpha (pT⍺) chain
  • Associated with with signal transducing CD3 molecules
  • Cells with productive TCRβ rearrangements and CD3 are rescued from apoptosis
  • The pre-TCR induces expansion and differentiation of these cells such that they become TCRαβ bearing CD4+8+ thymocytes
18
Q

How many attempts to make a single productive alpha chain

A

Many, not just a single attempt

19
Q

What does a common double negative T cell progenitor give rise to

A

αβ and γδ T cells

20
Q

Thymocyte development

A
  • Develops into o ⍺:β or γ:δ T cell
  • First rearrangement is either β chain or γ:δ (rearrangement happens at same time, first successful rearrangement determines cell lineage)
  • Gene rearrangement stops at this point (cells proliferate and express both CD4 and CD8 - double
    positive thymocyte)
  • Rearrangement of ⍺ chain can now proceed (competitive γ:δ rearrangements can continue
  • End result is committed ⍺:β or γ:δ T cell
  • ⍺:β T cell is double positive CD4+ CD8+
  • TCR is tested in a selection process that occurs in association with medullary epithelial cells MEC
21
Q

Early development of ⍺:β T cells in thymus

A

Progenitor cells –> Proliferation –> double negative T cells commit to T lineage –> rearrange β genes –> proliferating double negative pre T cells –> immature double positive cells –> rearrange ⍺ genes –> mature double positive cells

22
Q

Where to TCRs concentrate diversity

A

In third hypervariable region

23
Q

Central tolerance

A
  • Autoreactive cells are removed in the thymus
  • Double positive CD4+ and CD8+ thymocytes undergo further selection to develop into fully mature CD4+ or CD8+ T cells
  • Positive selection occurs in the thymic cortex
24
Q

What molecules do cortical epitheial cells express

A

MHC Class I and MHC Class II molecules expressing self peptides

25
Q

What determines whether a thymocyte will become CD4+ or CD8+ T cell

A

Positive selection (e.g. if receptor binds self peptide: self MHC class 1, it’ll become a CD8 T cell)

26
Q

The autoimmune regulator gene AIRE

A
  • Part of a complex that regulates the expression of tissue restricted antigens (TRAs) in medullary thymic epithelial cells (MTECs).
  • Peptides derived from these antigens are displayed on the MTEC and recognised by immature antigen-specific T cells, leading to the deletion of many self-reactive T cells.
27
Q

What happens in absence of AIRE

A
  • Immature self reactive T cells are not eliminated
  • Leads to autoimmunity
28
Q

What is negative selection mediated by

A

APCs

29
Q

Negative selection

A
  • Single positive CD4+ or CD8+ cells
    move from cortex to medulla
  • Come in contact with DCs and macrophages at the corticomedullary junction
30
Q

What is negative selection dependent on

A
  • Strength of TCR/MHC binding
  • Strong/tight binding = apoptosis is induced
  • Low/moderate binding = survival
31
Q

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED)

A
  • Caused by a number of different mutations in the gene that encodes autoimmune regulator
    (AIRE)
  • Characterised by damage to endocrine organs and chronic mucocutaneous Candidiasis
32
Q
A