Chapter 7

Question 1

How is thymus adjusted for T cell development?

Answer 1

• primary lymphoid organ -> immune cells development (no role when infection starts)
• bone marrow stem cells (progenitor cells) migrate to thymus
• immature T cells - thymocytes
  
  • mature in a network of epithelial cells = thymic stroma
• consists of 2 parts:
  
  • cortex (outer)
    
    • T cell dense
  • medulla (inner)
    
    • less dense
• progenitors become either thymocytes or dendritic cells
  
  • T cell progenitors enter junction between cortex and medulla
    
    • move through cortex outward -> back to inner cortex -> medulla (during differentiation)
• bone marrow-derived macrophages also migrate to thymus -> mainly in medulla
• fat gradually replaces thymus as we’re getting older
  
  • T cells are long-lived, self-renewing

Question 2

How are progenitor cells stimulated into T cell development?

Answer 2

• interaction with thymic stroma -> lose stem cell markers -> express T cell-specific adhesion mol (CD2, CD5, etc)
  
  • thymic stroma secretes IL-7 for stimulation
• no T cell receptor complex yet -> rearrangement of genes starts
  
  • these are called double-negative thymocytes (DN)
• Notch1 = thymocyte cell-surface recerptor interacts with transmembrane protein ligands on thymic epithelial cells
  
  • T cell differentiation
  • extracellular domain binds ligands -> intracellular domain detached -> becomes transcription factor

Question 3

What is the sequence of gene rearrangements that determine the lineage of T cell?

Answer 3

• rearrangements of γ, δ, and β first
  
  • compete to make T cell receptor
  • if γ + δ first, γδ T cell created
  • if β first -> incorporated into pre-T cell receptor
  • gene rearrangement stops -> CD4 and CD8 expressed = double-positive (DP) thymocytes
• then α, γ, δ compete -> depending which first T cell is formed
• only 2% of T cells succeed, rest dies by apoptosis

Question 4

What happens after T cell commits to γδ lineage?

Answer 4

• receptor assembled with CD3 signaling complex
  
  • signals to stop gene rearrangement
• γδ T cells leave thymus -> circulation

Question 5

What happens when β-chain genes are rearranged first?

Answer 5

• more common
• β chain tested by binding to pTα (surrogate chain) ->
  
  • 2 heterodimers (β+pTα) form a superdimer
  • testing whether functional receptor can be made
• each heterodimer assembles with CD3 complex and ζ chain -> pre-T cell receptor
  
  • CD3 complex and Lck send a signal -> stop gene rearrangements -> becomes pre T cell
    
    • RAG complex degraded

Question 6

What happens after β chain formation?

Answer 6

• α chain made (or γδ but very unlikely)
• once synthesised, capacity to bind B chain tested -> if successful, is a subject to positive selection
• α-chain gene rearrangements made until functional chain produced

Question 7

What is positive selection of T cells?

Answer 7

• only T cells with receptors complementary to self MHC are selected
• MHC class I and II expressed by cells of thymus loaded with proteins from normal degradation -> antigens presented
  
  • double-positive T cells binding selected
• MHC restriction => MHC isoform mediates positive selection of a T cell (this T cell can only respond to that MHC)

Question 8

What is the function of thymoproteasome and how can it affect positive selection?

Answer 8

• proteasome in cortical epithelila cells of thymus -> produces self peptides for self MHC
  
  • effective binding to MHC class I
• differs by immunoproteasome by a β5 subunit
• β5 has a variant which will not form active proteasome -> reduction in number of CD8 T cells -> hinders positive selection

Question 9

How are single positive thymocytes created?

Answer 9

• T cell receptor + co-receptor (with CD3) interact with peptide:MHC complex
• if MHC class I, cluster contains CD8 only
• if MHC class II, CD4 only
• signals sent by co-receptors (Lck) -> commitment to CD8 or CD4 lineage

Question 10

What is negative selection?

Answer 10

• T cells that bind too strongly to self-peptide:MHC complex on dendritic cells and macropahges -> apoptosis (potentially autoreactive)

Question 11

How is negative selection specified to T cells that bind self-antigens found outside of thymus?

Answer 11

• subpopulation of epithelial cells have transcription factor = autoimmune regulator (AIRE)
  
  • tissue-specific proteins expressed
  • peptides bind to MHC class I -> negative selection produces central tolerance
• peripheral tolerance (T cell binds self-antigen outside of thymus) are made anergic

Question 12

What are regulatory CD4 T cells?

Answer 12

• recognise self antigens
  
  • express CD25, use transcriptional repressor FoxP3
• when bound to MHC class II with self antigen they suppress activation of other T cells responding to this self antigen
• exact mechanism unknown

Question 13

How do mature T cells differentiate?

Answer 13

• antigen recognition in secondary lymphoid tissues
• differentiate into effector T cells
• many types of effector cells
  
  • cytotoxic T cells
  • regulator T cells
  • helper T cells (many types of helper cells)