10 - T Cell Effector Responses Flashcards
T cell pathway
- T cell precursor rearranges its T cell receptor genes in the thymus
- Immature T cells that recognise self MHC receive signals for survival. Those that interact strongly with self antigen are killed
- Mature T cells encounter foreign antigens in the peripheral lymphoid organs and are activated
- Activated T cells proliferate and eliminate infection
Naive T cells
- T cell has not previously encountered its cognate antigen
- Antigen is brought to lymph node by dendritic cell that has sampled antigen in periphery
- Naïve T cell that encounters cognate antigen is activated
and undergoes clonal expansion, differentiates into effector or memory cells
Cognate antigen
Antigen that best fits the specific T cell receptor
Effector T cells
- Enter circulation and traffic to sites of infection in peripheral tissues
- Effector cells that encounter antigen in the periphery are further activated to mediate their effector functions
What is activation and movement of T cells mediated by
Cytokines and chemokines
3 major processes that must occur after antigen recognition
- Produce cytokines and cytokine receptors (e.g. IL-2) –> Proliferation
- Proliferate and undergo clonal (TCR with same specificity) expansion
- Differentiation into effector (short lived) or memory (long lived) cells
Lymphocytes in blood entering lymphoid tissue
- Cross walls of high endothelial venules (HEV)
- CCL21 is expressed by HEV and stromal cells of lymphoid tissues and binds CCR7 on naïve T cells
- Contact of naïve T cells with CCL21 in the HEV causes the integrin LFA-1 on the naïve T cell to become activated, increasing its affinity for ICAM-1
- Activated LFA-1 binds tightly to ICAM-1
- Lymphocyte migrates into lymph node by diapedesis
What cells stimulate naive T cells
B7 expressing DCs
What molecule indicates that a DC has seen an antigen
B7
Process of T cells encountering an antigen
- Naïve T cells enter lymph nodes from arterial blood via specialised endothelial cells called high endothelial venues (HEV)
- T cells migrate into paracortical areas where they encounter dendritic cells
- T cells that do not encounter cognate antigen leave node via lymphatics and return to circulation
- T cells that encounter cognate antigen become activated to proliferate into effector cells. They lose ability to exit lymph node
- After a few days effector cells regain ability to leave nodes and leave via efferent lymphatics and enter circulation
Naive T cells and dendritic cell interactions
- T cell initially binds DC through low affinity LFA-1 : ICAM-1 interactions
- Subsequent binding of T cell receptors sends signal to LFA-1
- Conformational change in LFA-1 increases affinity and prolongs cell to cell contact
Nursery
Satellite DC maintains contact with all clones
How long does it take for activated effector T cells to leave the lymph node after arrival of antigen
5 days and leave via efferent lymphatics
Trapping
All naïve T cells specific for a particular antigen can be trapped by that antigen (presented via DC) in node within 2 days
3 signals delivered by APCs to activate T cells
- Antigen presentation (MHC/peptide to TCR): activation
- Co-stimulatory molecules: Survival
- Cytokines: Differentiation
Antigen presentation signals
- MHC class 1/peptide to CD8+ T cell
- MHC class 2/peptide to CD4+ T cell
Co-stimulatory molecules
- CD28 on T cell to B7 (CD80/ CD86) on DC
- CTLA-4 on T cell to CD80/CD86 on DC for homeostasis
Cytokine signals in activation
- T cell proliferation (IL-2)
- T cell lineage differentiation (cytokines produced by APC, mostly DC)
Examples of cytokines involved in activation of naive T cells
- IL-4
- IL-6
- IL-12
- TGF-β
Variation in signal 3 (cytokines)
Causes naive T cells to acquire several distinct types of effector function
Treg Cells
Down-regulate effector responses
Tfh Cells
Found in germinal centre lymph nodes, assist B cells
Th17 cells
Importnat in neutrophil function
Th1
Supporting cell mediated immunity (macrophages)
Th2
Supporting cell mediated immunity (macrophages) and support B cells
Which two cytokines down regulate T cell immunity
- TGF-β
- IL-10
- Secreted by Treg cells
Cytokines and transcription factor that cause differentiation of Treg cells
- TGF-β
- FoxP3
Cytokines and transcription factor that cause differentiation of Tfh cells
- IL-6
- Bcl6
Cytokines and transcription factor that cause differentiation of Th17 cells
- TGF-β and IL-6
- RORγT
Cytokines and transcription factor that cause differentiation of Th1 cells
- IL-12 and IFN-γ
- T-bet
Cytokines and transcription factor that cause differentiation of Th2 cells
- IL-4
- GATA3
Why have human evolved multiple subsets of T cells
To protect against different classes of pathogens
What do Tfh cells secrete
IL-21 and ICOS
What do Th17 cells secrete
IL-6 and IL-17
What do Th1 cells secrete
IL-2 and IFN-γ
What do Th2 cells secrete
IL-2 and IL-5
How do CD8+ cytotoxic T cells kill target cells
- A pore is created in target cell by CTL perforin
- Granzymes delivered through pore induce caspase- dependent apoptosis pathways
CD4 T cell help in activating CD8 T cells
- APC stimulates effector CD4+ T cell to induce expression of CD40L and IL-2
- Effector CD4+ T cell recognises antigen on the APC and is triggered to induce increased levels of co-stimulatory activity on the APC (increased B7 and expression of 4-IBBL)
- 4IBBL ligates 4-IBB on CD8+ T cell (this enhances activation of CTL)
- The CD4+ T cell also produces IL-2 that drives proliferation of CD8+ T cells
TCR ligation with MHC/peptide complex in absence of CD28/B7 co-stimulation
- Induces anergy (state of unresponsiveness that is irreversible)
- Through decreased signalling by induction of GRAIL and activation of Cbl
Role of CTLA-4
- Contraction and re-establishment of homeostasis
- CTLA-4 binds B7 more avidly than CD28 and delivers inhibitory signals to activated T cells
How does CTLA-4 outcompete CD28
A distinct binding orientation allows one dimer of CTLA-4 to bind two different B7 dimers, providing for high avidity clustering
CTLA-4 In cancer therapy
- Binding of B7 to CTLA-4 inhibits T cell function
- Anti–CTLA-4 antibodies block CTLA-4 binding and prevent inhibition of T cell function (checkpoint inhibitor)
When does activation and co stimulation occur
At time of priming (co-stimulation not required for recognition of antigen at infection site)
Th1 cell function
- Macrophage activation
- Complement binding and opsonising IgG antibodies
Responses of activated macrophages to Th1 cells
- Enhanced killing of phagocytosed bacteria
- Secretion of inflammatory cytokines
- Increased expression of molecules required for T cell activation
Function of Th2 cells
- Antibody production (helminth parasites too big to be phagocytosed)
- Mast cell degranulation
- intestinal mucus secretion and peristalsis
- Eosinophil activation
- Alternative macrophage activation (enhanced tissue repair)
Th2 cytokines role in macrophage activation
Th2 cytokines inhibit classical macrophage activation (microbicidal) and stimulate the alternative pathway of macrophage activation (anti-inflammatory, tissue repair)
Function of Th17 cells
- Innate response
- Inflammation, neutrophil response
- Anti-microbial peptides
- Increased barrier function
Regulatory T cells (Treg) function
Suppress and prevent immune responses (eg. to self antigens: maintains tolerance) through inhibition of T cell activation and T cell effector function
Decline of immune response
- Once immune response is over, system must return to steady state (homeostasis)
- Once infection is cleared, cells are deprived of stimuli and survival signals
- Cells die of apoptosis
- Response subsides within 1-2 weeks after infection is eradicated
- Pool of memory cells remains
