T cell activation by antigens

Question 1

What are naive T cells?

Answer 1

Naïve T cells- mature T cells that have left the thymus, but have not been exposed to their specific antigens
o Have not undergone clonal selection and expansion triggered by antigen exposure

Question 2

How does naive T cell activation occur and what does it result in?

Answer 2

o Naïve T cell activation occurs when the cell is stimulated with antigen and additional signals
o When a T cell undergoes activation, it becomes an effector T cell, which means it has gained additional functions to orchestrate an adaptive immune response.

Question 3

What is the role of pDCs (dendritic cells)

Answer 3

o Dendritic cells-
 Initiate inflammation in response to microbes
 Initiate adaptive immune responses to microbes (T cell mediated responses) by capturing antigens and delivering them to lymph nodes

Question 4

How do pDCs get activated?

Answer 4

o DCs take up microbes and microbial proteins and break them into peptides
 The dendritic cell will internalize the microbe/or proteins made by the microbe (even after the microbe’s death) to degrade those proteins into peptides
o DCs are activated by PAMPs
 Through toll-like receptor: in response to microbes, DCs are activated

Question 5

How do activated dendritic cells go to the lymph node and activate T cells?

Answer 5

o Activated DCs express surface molecules that are important for T cell activation
 One of these molecules is called the MHC molecule that has a peptide that has protein derived from a microbe
 The other molecule is called a co-stimulator
o Activated DCs migrate through the lymphatic system to lymph nodes
 Chemokine receptors (CCR7) is expressed on the activated DC
* This chemokine receptor will recognise a chemokine made by the lining of the endothelial cells of the lymphatic vessel-> this will make the activated DC go into the lymphatic vessel-> the lymph (including the DC) of the lymphatic vessel drains into our body’s lymph nodes

Question 6

Where does naive lymphocyte activation occur and why?

Answer 6

• Naïve lymphocyte activation occurs primarily in secondary lymphoid organs like lymph nodes, spleen and mucosal lymphoid tissues
  o This is because both the dendritic cell carrying microbe-derived protein (which came through the lymph) and the naïve T cell (which came through the blood vessels) meet there
• Lymph nodes are the place where naïve T cell activation occurs because:
  o There are very few naïve T cells specific for a microbial antigen-> since infection can occur anywhere in the body, lymph nodes are common meeting places for antigens and T/B lymphocytes

Question 7

What are T cell co-receptors and what do they do?

Answer 7

• Co-receptors: molecules on the T cell that bind to the MHC molecule presenting a peptide antigen to the T cell receptor and which facilitate signalling by the TCR

Question 8

What are 2 main class of T cells/naive T cells and what do they do?

Answer 8

main classes of T cells/naïve T cells:
o CD4+ T cells: helper T cells which have numerous immune functions
o CD8+ T cells: attack and directly kill infected and cancerous cells

Question 9

How do naive T cells migrate to lymph nodes?

Answer 9

• Naïve T cell recirculation
  o Naïve T cells constantly circulates through the body
  o This involves naïve T cells going in and out of lymph nodes
   The high endothelial venule (HEV) has special characteristics that allows naïve T cells to bind to their walls and enter lymph node tissue

Question 10

What are the characteristics of high endothelial venule (HEV) that allow recirculation of naive T cells?

Answer 10

 The characteristics of this HEV include:
* Surface display of chemokines and adhesion molecules which naïve T cells can bind to because they have the right chemokine receptor (such as CCR7) and adhesion molecule
* These characteristics are unique to HEV- which means that naïve T cells will not exit the circulation anywhere else but these lymph nodes

Question 11

What are the two main regions of the lymph node and what kind of cells do they contain?

Answer 11

• Two regions in the lymph nodes:
  o Follicular region- for B cells
  o Interfollicular region- for T cells

Question 12

How do the activated dendritic cell and the naive T cell meet for T cell maturation and how does this meeting result in T cell maturation?

Answer 12

• How the dendritic cell and the naïve T cell will meet is that both have chemokine receptors that bind to CCR7 in the interfollicular region-> this will bring them together
  o If the naïve T cell happens to have an antigen receptor (TCR) that can bind to this particular peptide MHC antigen, where the peptide is from a microbial protein, the T cell will bump into that dendritic cell as its moving around in the area of the lymph node, it’ll get signals that’ll activate and cause proliferation of the T cell-> process of clonal expansion
  o However, if the T cell doesn’t see the antigen because it doesn’t correspond to its receptor, it won’t be activated and will exit the lymph nodes via lymphatics, enter the circulation starting the process of free circulation throughout the arterial tree visiting any other lymph nodes of which there are hundreds in the body
   Recirculation ensures that any naïve T cell will ultimately find an antigen which it is specific for in the body

Question 13

What is the purpose of costimulation for naive T cell activation?

Answer 13

• Costimulation-ensures T cell activation only occurs when danger/microbes are present
• The two signal requirement protects us from developing an immune response against self

Question 14

What two signals does naive T cell activation require?

Answer 14

o Signal 1 is an antigen, which is the peptide-MHC complex recognized by a specific T cell
o Signal 2 is costimulation, which is provided by an activated antigen presenting cell (APC). APCs are activated only when they encounter PAMPs

Question 15

How does signal 1 of T cell activation occur?

Answer 15

 T cell receptor (TCR) recognises peptide antigen (peptide derived from microbial protein on antigen presenting cells such as dendritic cells)
 This makes the CD4 or CD8 molecule engaged-> leads to signalling that will make biochemical changes in the T cell-> these signals are required for T cell activation

Question 16

How does signal 2 of T cell activation occur?

Answer 16

 PAMPs bind to innate pattern recognition receptors (TLRs) on dendritic cells-> this leads to expression of co-stimulatory molecules which bind to costimulatory receptors (such as CD28) on the naïve T cells
* Examples of common costimulatory molecules include B7-1 (such as CD80) and B7-2 (such as CD86)

Question 17

What does T cell activation result in?

Answer 17

• T cell activation means clonal proliferation and differentiation of this specific T cell which leads to an army of effector T cells

Question 18

What happens if 1 signal happens in T cell activation without the other signal being there?

Answer 18

o If signal 1 (antigen) occurs without signal 2 (costimulation), T cells will not be activated
o Without both signals, T cells will either die by apoptosis or become anergic (unresponsive)

Question 19

What are anergic T cells and what does this protect us from?

Answer 19

 Anergic-when the T cell becomes unresponsive to antigen on a subsequent exposure
* This protects us from self-activation if that self-exposing dendritic cell ever gets exposed to a microbe PAMP and expresses those costimulatory molecules

Question 20

How could self-reactive T cells be activated if there was no costimulation rule?

Answer 20

• Some T cells recognise our own peptides/proteins- don’t want these to get activated
  o These T cells are called self-reactive T cells
• Some dendritic/antigen presenting cells internalise and lyse some of our own proteins->put those peptides on MHC molecules on the surface-> BUT there are no costimulatory molecules because no PAMPs

Question 21

How does T cell proliferation get controlled and why?

Answer 21

• As proliferation increases, T cells start exposing an inhibitory molecule on their surface called CTLA-4
• Inhibitory receptors dampen T cell activation
• These inhibitory receptors protect us from excess inflammation/killing

Question 22

What signals dampen T cell activation and how?

Answer 22

• Inhibitory receptors dampen T cell activation
  o CTLA-4 displaces CD28 as it is a higher affinity to B7 compared to the CD28 molecule, and binds to B7 molecules, thus blocking CD28 signalling: this attenuates T cell activation in lymph nodes
  o PD-1 signalling leads to T cell ‘exhaustion’ in tissues: at sites of infection and in tumours
   PD-1 on T cell binds to PD ligand on infected cell
   T cells upregulate PD-1
   PD-1 interaction with PD ligand transforms cells that were ready to kill into exhausted T cells (cells that want to sleep)
   Tumours or chronic viruses evade the immune system by relying on PD1 signalling

Question 23

What are the 2 degradative compartments in a cell? Describe their degrative compartments and how they work

Answer 23

There are 2 degradative compartments in a cell:
1. Lysosome/secretory pathway
a. Accepts proteins coming from either within or outside the cell
b. Part of the secretory pathway where proteins are bound by a lipid bilayer
c. Connected to the outside of the cell
d. Protein binds to surface-> internalized in a vesicle-> vesicle fuses with lysosome-> protein degraded into peptides
2. Cytosol
a. Only at the inside of the cell
b. Proteasome (made up of 28 proteins) is a cap that accepts proteins that are marked for degradation-> proteins are degraded and chopped into peptides in the cytosol

Question 24

What is antigen presentation?

Answer 24

Antigen presentation- when an antigen-presenting cell displays a peptide on an MHC molecule

Question 25

What are the 2 pathways of antigen presentation?

Answer 25

• Lysosomal peptides load onto MHC class II molecules and are recognized by CD4+ T cells
• Proteasomal peptides load onto MHC class I molecules and are recognized by CD8+ T cells

Question 26

Describe the MHC class II pathway including: site of degradation, peptide loading, cell type and what cell it’s recognized by:

Answer 26

Site of degradation is lysosomes
* Lysosomal peptides load onto MHC class II molecules and are recognized by CD4+ T cells
o MHC class II molecules are synthesized in the ER-> come through Golgi-> reaches lysosome containing degraded peptide-> binds to peptide that binds tightly to the groove-> once occupied by peptide, goes to the surface of the cell
o CD4 itself also binds to the class 2 molecule
o MHC class II is on dendritic cells, B cells and macrophages

Question 27

Describe the MHC class I pathway including: site of degradation, peptide loading, cell type and what cell it’s recognized by:

Answer 27

Site of degradation: proteasome
* Proteasomal peptides load onto MHC class I molecules and are recognized by CD8+ T cells
o Protein marked for degradation by ubiquination-> protein enters the proteasome and is degraded by the chamber into peptides-> peptides transported into endoplasmic reticulum by channel called TAP transporter (transporter of antigen processing) which takes peptides that have come out of proteasome and puts them into lumen of endoplasmic reticulum
o MHC Class I molecule made in ER binds to appropriate peptide->egresses the ER-> buds out into vesicle-> binds to Golgi and emerges from the Golgi to the cell surface
o CD8 protein binds to the class I molecule
o MHC class I is on all nucleated cell because any cell can be infected by a virus so killer T cells need to be able to see it