Lecture 21 - T cells - Cellular Interactions & Trafficking Flashcards
What is a naïve T cell?
Fully developed
Yet to be activated by cognate antigen
Describe circulation of naïve T cells
How long does each circulation last?
Constant recirculation through lymphoid organs
- Leave thymus
- Enter blood
- Enter lymphoid organ via HEV
- Sample MHC:peptide complexes on DCs in the LNs
– do not experience cognate antigen –
- Leave lymphoid organ via efferent lymphatics
- Circulation through more lymphoid organs
- Eventual draining into thoracic ducts (blood)
- Return to lymphoid organs
Full circle every 24 hrs
In a given lymphoid organ, if the T cell does not encounter its antigen, it departs via the efferent lymph and continues circulating
This circulation increases the likelihood that the T cell encounters the correct DC
Describe the interactions in naïve T cells homing to lymphoid tissues
(Similar to neutrophil recruitment)
Margination
• Slower moving blood
- Rolling - Selectins
- L-selectin on T cell
- GlyCAM1 and CD34 on HEV
- MAdCAM1 on endothelium in gut associated endothelium
- Activation - Chemokines
• CCR7 on T cells
• CCL21 released by LN stomal cells - Adhesion - Integrins
• LFA-1 on T cells
• ICAM-1 on endothelium - Diapedesis - Chemokines
• CCL21 and CXCL12 released by LN stomal cells
• CCR7 on T cells
Where are naïve T cells never found?
Never found in the tissue Also: • Liver • Testis etc. Thus, they are never in the afferent lymph of the first LN
They may however be in the afferent lymph entering following LNs
Why is it necessary to have selectins and integrins in recruitment of lymphocytes?
High blood pressure, need some force to select out the cells
Describe the molecule interactions in ‘Rolling’ of naïve lymphocytes into 2° lymphoid organs
Selectins on T cells interact with Addressins on the endothelium of the lymphoid organ
- Selectins:
Lymphocyte: L-selectin - Addressins
HEV: GlyCAM-1 and CD34
Endothelial cells in GALT: MadCAM-1
What determines when lymphocytes will roll along the margin of blood vessels?
Signals result in expression of selectins on the surface (inside-out signalling)
Cells become ‘sticky’
Describe the molecule interactions in ‘Adhesion’ of naïve lymphocytes entering 2° lymphoid organs
Lymphocyte: LFA-1
Endothelial cells: ICAM-1
Compare the interactions of selectins & integrins
Selectin:
• Selects a T cell to become capable of integrating into the tissue
• First step
Integrin:
• Binds the T cell very tightly to the endothelial
• Second step
How do naïve T cells enter LNs?
Through HEV
Which chemokines attract naïve T cells to LNs?
CCL19 & CCL21 via CCR7
What is the role of stromal cells in lymphoid organs?
Made up much of the structure in lymphoid organs
Play an important role in immunity
Produce chemokines that attract naïve T cells (as well as activated DCs) into lymphoid organs
What does it mean if a T cell expresses CCR7?
Classified as naïve
Is able to move into lymphoid organs through interaction with chemokines
Where are HEVs?
In the paracortex of LNs
What brings activated DCs into the LNs?
Drain into LN in the afferent lymph into paracortex
Upregulation of CCR7 so that they know follow CCL19/CCL21 gradients to the LNs
Describe the cooperation between mature DCs from tissue & resident DCs in LNs
- Langerhans cell in skin takes up Ag
- Langerhans cells drain to LN
- Enter via afferent lymphatics
- Transfer of some antigens from mature DC to resident DCs
- Resident DC stimulation of naïve T cell
Describe the interaction between naïve T cells and DCs
Integrin interaction
• Very tight binding
• Last up to 12 hours
‘Immunological synapse’
Adhesion: LFA1 (T cell) + ICAM 1 (DC)
- Signal 1
• TCR/CD3/CD4/CD8 + MHC/peptide
• In the centre
2. Costimulatory molecules • Numerous • Not antigen specific • Only start to interact after Signal 1 • Interaction delivers the stimulation into the naïve T cell • around the periphery of the synapse e.g.: • CD28 + CD80/CD86 • CTLA4 + CD80/CD86
Describe distribution of costimulatory molecules in the naïve and mature state
Naïve:
• TCRs evenly distributed around the surface of the T cell
→ TCR encounters MHC+peptide on DC
Mature:
• Migration of all TCRs towards region where TCR encountered antigen
• Aggregation in centre
What is the key growth factor for activated T cells?
IL-2
Stimulates cell to enter cell cycle
i.e. Signal 3
Compare naïve and mature T cell responsiveness to IL-2
Naïve:
• Can respond, but only very poorly
• Moderate affinity IL-2R
• γ (CD132) and β subunits
Activated:
Expression on CD25 (α subunit) → High affinity IL-2R
• α, γ and β subunits
What is DC licensing?
CD4+ T cell response required for CTL response
Mechanism:
- CD4+ T cell stimulates and ‘licenses’ DC through CD40-CD40L interaction
- DC better able to stimulate CD8+ T cells
Describe signal 3
- DC starts releasing IL-2
- IL-2 binds IL-2R on T cell
- T cell proliferation
Describe the events that occur to allow T cells to leave LNs after activation
- T cells down-regulate CD69
- S1P1 receptor is up-regulated
- S1P1 present in efferent lymph, chemotactic factor
- T cells move out into efferent lymph towards S1P1
NB: also down regulate:
• CCR7
• CD62L
Describe retention of T cells in LNs during activation and proliferation
- Once activated, T cells express CD69
- This inhibits S1P1 receptor expression on the T cell
- T cell is stuck in the LN
What is CD25?
The α component in the high affinity IL-2R
What is the immunological synapse?
Interaction between APCs and naïve T cells
Adhesion molecules:
• LFA1 - ICAM1
Antigen presentation:
• MHC+peptide - TCR
Co-stimulation:
• CD28 - CD80/CD86
• CTLA4 - CD80/CD86
Describe the structure of the high affinity IL-2R
α chain; CD25
β chain; CD122
γ chain (γc chain, CD132)
How does the immunological synapse last?
12 hours
What is CD62L?
When is it expressed by T cells?
aka L-selectin
Expressed on naïve T cells, as it localises them to the LNs
Down-regulated once gained effector function
