Chapter 8

Question 1

How are T cells activated when an infection starts?

Answer 1

• dendritic cells bring antigens to secondary lymphoid tissues
• immature dendritic cells: process and present antigen
• in cortex of lymphoid tissues become mature -> instead of previous functions they now activate T cells
  
  • dendrites used for interactions with T cells

Question 2

What is the role of macrophages in lymph nodes during infection?

Answer 2

• phagocytosis of pathogens in afferent lymph
• pathogens can’t leave lymph and enter the blood

Question 3

How are external pathogens endocytosed by DCs?

Answer 3

• receptor-mediated endocytosis
  
  • pathogen binds to receptor -> endocytosed with small amount of extracellular fluid = micropinocytosis
• nonspecific endocytosis (no binding to receptor) of larger volumes of fluid = macropinocytosis
• peptides from processed pathogens on MHC class II

Question 4

How do T cells enter lymph nodes?

Answer 4

• through high endothelial venules (HEVs)
• T cells bind to endothelial cells and squeeze -> enter cortex (most outward part) of lymph node = T-cell area
  
  • interaction with dendritic cells
• if no antigen match found, T cells leave node and carried to ‘downstream’ part
  
  • enter through afferent lymphatic vessels

Question 5

How are T cells homed?

Answer 5

• process by which naive T cells enter T cell area from blood
  
  • chemokines secreted by DCs and stromal cells: CCL21 and CCL19
  • T cells have CCR7 receptor for those chemokines
• first interaction: cell-adhesion molecules
  
  • L-selectin on T cell surface binds to vascular addressins CD34 and GlyCAM-1 on HEVs
  • contact strengthened by additional adhesion mol (LFA-1 binding with ICAM-1 and ICAM-2)
  • interaction with chemokines strenghtens binding of adhesion mol
• T cells on HEVs move toward source of chemokines (squeeze)

Question 6

How do T cells bind to dendritic cells?

Answer 6

• adhesion molecules (both on T cells and DCs) bind to adhesion receptors (also on both cells)
  
  • DC-SIGN = adhesion mol unique for DCs
  • strengthened by CD2 ans LFA-3
• this enables T cells to access peptide:MHC complex -> once bound LFA-1 ad ICAMs interaction stronger = form cognate pair
• this induces T cell proliferation -> diff into effector cell

Question 7

How do mature T cells leave lymph node?

Answer 7

• when bind to antigen start producing S1P receptor
• S1P gradient created -> guides T cells out of lymph node

Question 8

What signals are needed for activation of T cell?

Answer 8

• antigen receptor
• co-receptor (CD4 or CD8)
• co-stimulatory receptor (CD28) that binds to B7 on dendritic cells
  
  • at the same as when peptide:MHC is bound

Question 9

What is the role of ZAP70 in T cell signalling?

Answer 9

• activated by phosphorylated Lck
• binds to ζ chains to be phosphorylated -> starts cascade

Question 10

What is the role of cytokine interleukin-2 (IL-2)?

Answer 10

• autocrine: secreted by activated T cells, acts on naive T cells
  
  • gene transcription of IL-2 activated by signalling from T cell receptor, co-receptor and co-stimulatory receptor
  • when activated naive T cells start production of IL-2 receptor
• stimulates them to proliferate and differentiate

Question 11

What happens to T cells that bind self antigens but were not recognised during negative selection?

Answer 11

• bind to self antigen outside of thymus
• lack of B7 (only on APCs) -> co-stimulatory receptor not stimulated
  
  • binding causes anergy
  • T cell cannot produce IL-2 => irreversible

Question 12

What are the five types of effector CD4 T cells?

Answer 12

• TH1: activate macrophages (intracellular infection)
• TH2: activate eosinophils, basophils, mast cells, B cells (IgE production) (parasites)
• TH17: enhance neutrophil response to extracellular bacterial / fungal inf
  
  • produce IL-17
  • epithelial and stromal cells produce CXCL8 -> recruitment of neutrophils
• TFH (follicular): actiavtion of naive B cell -> into plasma cells
• Treg (regulatory): supress other T cells
  
  • stimulates tissue repair after immune response
• CD4 T cell properties can change depending on environment

Question 13

How do T cells differentiate into TH1?

Answer 13

• increase inflamm
• stimulation by cytokines prod by DCs and macro: IL-12, NK cells: IFN-y
• first TH1 cell produces more IFN-y -> positive feedback

Question 14

How do T cells differentiate into TH2?

Answer 14

• IL-4 response (from basophils)
• first TH2 produces IL-4 and IL-5 -> positive feedback

Question 15

How do T cells differentiate into TH17?

Answer 15

• IL-6 and TGF-B -> induce IL-21 production
  
  • autocrine, induces transcription factor for TH17 differentiation
• TH17 most inflammatory (responsible for autoimmune diseases)
• in later stages IL-23 also needed -> stimulates production of IL-17 by TH17

Question 16

How do T cells differentiate into TFH?

Answer 16

• IL-6
• co-stimulation by DCs with ICOS
  
  • ICOS ligand binds to DCs
• TFH cells express CXCR5 (receptor for CXCL13 -> chemokine produced by stromal cells of B-cell follicle)
  
  • binding causes TFH to leave T cell areas -> B cell areas
  • cytokines secreted by TFH -> B cell isotype switching

Question 17

How do T cells differentiate into Treg?

And what are the two types of Treg cells?

Answer 17

• natural Treg -> during T cell development in thymus
• induced Treg -> in periphery during immune response
  
  • when other effector cells activated by TGF-B but there is lack of IL-6 -> T cells differentiate into Treg
  • presence or lack of inflammatory cytokines determines whether T cell will differentiate into Treg or TH17 (due to TGF-B)
• Treg express FoxP3, CD4 , CD25
• produce TGF-B IL-10 -> stop inflammation

Question 18

What does it mean that effector T cells are polarised?

Answer 18

• positive feedback in differentiation of TH1 or TH2 cells causes rapid expansion and domination of one type of T cell
• TH1: cell-mediated immunity
• TH2: humoral immunity (based on antibodies)

Question 19

What happens when DCs are not sufficient to activate naive CD8 T cells?

Answer 19

• virus-specific effector CD4 T cell needed
• CD4 T cells binds to MHC class II on DCs with viral peptide -> secretes IL-2
  
  • IL-2 binds to receptors on CD4 T cell and CD8 T cell nearby (that binds to MHC class I)
  • signal from MHC class I binding, co-stimulatory receptor and IL-2 activate CD8 T cell
• CD8 T cells damage tissue -> activation has to be controlled

Question 20

What is a key difference between naive and effector T cell adhesion molecules?

Answer 20

• no L-selectin on effector (no binding to secondary lymphoid tissue)
• presence of VLA-4 -> binds to VCAM-1
  
  • expressed by endothelial cells of blood veon sites of inflammation
• more CD2 and LFA-1 cell-adhesion molecules -> ICAM-1 and LFA-3 binding stronger
• effector T cells do not need co-stimulatory signal
  
  • for naive cells lack of this signal = anergy

Question 21

How do cytokines work with JAKs pathway?

Answer 21

• cytokine binding assembles a receptor on target cell surface
  
  • by bringing 2 proteins together
• JAKs (kinases) are associated with tails of receptors -> dimerise -> phosphorylate each other
  
  • phosphorylise STATs -> 2 STATs dimerise -> become transcription factor

Question 22

How are effects of cytokines turned off?

Answer 22

• intracell. phosphatases remove phosphate groups on JAKs, STATs and cytokine receptors

Question 23

How do CD8 T cells execute their functions?

Answer 23

• kill only antigen-bound cells
• secrete lytic granules in synapse only -> granules fuse with target cell -> no affect on neighbouring healthy cells
  
  • induce apoptosis -> no release of pathogenic particles
  • pores made in target cell -> granzymes (part of lytic granule) enter cell
    
    • production of nucleases -> degradation of DNA (cell’s and viral)
    • phagocytosis of the cell
• secrete cytokine IFN-y -> inhibits viral rep, increases presentation of viral antigens

Question 24

What is macrophage activation?

Answer 24

• TH1 binds to macrophages to enhance their function
  
  • through MHC class II on macrophages
• cytokines secreted
  
  • phagosomes fuse with lysosomes more efficiently
  • increased synthesis of microbicidal agents to capture pathogens

Question 25

What are the signals that activate macrophages?

Answer 25

• IFN-y binds to receptor on macrophages
• CD40 ligand = membrane-bound cytokine on TH1 cells binds CD40 on macrophage
• both affect gene expression
  
  • TH1 expresses cytokine genes (soluble and membrane-bound)
    
    • soluble delivered to synapse (antigen-specific) -> inflammatory response concentrated at site of infection not everywhere
• microbicidal substances can damage healthy cells -> effects stopped by TH2 (produces anti-inflammatory cytokines)

Question 26

How do Treg cells inhibit effector T cells?

Answer 26

• in secondary lymphoid tissue bind to DCs -> prevent activation
• direct contact with effector cell
• secrete anti-inflammatory cytokines
• FoxP3 unique for human Treg