L5: T Cell Activation Flashcards
How is clonal proliferation of naive T cells triggered?
By cells making contaact with specific Ag and APC in secondary lymphoid tissue
What effector cells do naive T cells differentiate into?
- cytotxic T cells (CD8+) which kills infected cells
- helper T cells (CD4+) which secretes cytokines
What happens in lymphoid tissue?
- T cells recognise Ag/MHC on APC
- T cells reside prior to activation
Where can APC be found?
In lymphoid tissue e.g. lymph nodes, spleen, tonsils
What must happen for naive T cells to survive?
They must encounter Ag
Explain the process by which T cells become activated
- Enter lymph node from blood via high endothelial venules
- Moves into ‘T cell area’ which is rich in dendritic cells and macrophages (APC)
- APC presents Ag and delivers other activation signals
- T cells that aren’t activated leave lymph node via cortical sinuses and lymphatic vessels, where they re-enter circulation and are recycled. If they are still unable to activate they die
What is the function of chemokine receptors on the T cell surface?
Chemokine receptors bind ligands (chemokines) expressed or released by other cells
How are cell/cell interactions mediated?
Using cell adhesion molecules (CAMs) once close to other cells
T cells contact APC using CAMs then TCR scans APC peptide/ MHC complexes. What 2 outcomes can occur?
- No recognition- disengages
- Recgonition- signal from TCR complex (CD3) sent, increasing affinity of CAMs interactions.
- T cells divide
- Progeny differentiate into effector cells and exit forming the T cell mediated response
Explain the T cell mediated response
- T cells bind APC through low affinity LFA 1/CAM 1 interactions
- Subsequent bnding of TCR signals LFA 1
- Conformational change in LFA 1 increases affinity and prolongs cell/cell contact, which is the start of the singalling cascade T cell receives
What molecule does the first signal of the T cell signalling cascade involve?
The CD3 zeta chain
What do naive T cells require for activation
3 signals
After T cell activation what proteins are expressed?
ICOS (Inducible T-cell COStimulator) & CTLA 4
What is the job of ICOS
It binds ICOSL on APC to induce cytokine secretion by T cells
What is the job of CTLA-4
Binds to B7, stronger than CD28 which it is highly related to, which delivers a -ve signal to the activated T cell (is antagonist to that of CD28)
What is the purpose of the -ve signal sent to T cell after CTLA-4 binding?
It dampens down/ limits T cell response
CTLA mutations are associated with what type of diseases?
Autoimmune diseases
Give an example of a clinical use of CTLA
It can be used to treat cancer patients by blocking negative signaling from the B7-CTLA-4 interactions, to enhance immune (B cell) response
Name 2 co-stimulatory molecules involved in the T cell response
- CD80 (B7.1)
- CD86 (B7.2)
They both seem important but their functional differences aren’t clear yet
What states can CD80 and CD86 be found in?
- Constitutive on mature dendritic cells
- Inducible on macrophages/ B cells
What triggers co-stimulation on APC?
Activation of APC by pathogens so APC can provide 2nd signal to activate T cells
What is the 2nd T cell activating signal also known as?
The danger singal
How is the danger signal activated?
APC expresses receptors for microbial molecules (PPR) and bind these pathogen- associated molecules. This ensures this signal only occurs during infection
What does the danger signal trigger?
The APC upregulation of MHC and co-stimulatory molecules
What will happen if a T cell receives signal 1 without signal 2?
It becomes functionally inactivated (anergic) and will not respond. This ensures only pathogen activated APC can activate T cells
How is signal 3 delivered?
It is provided by cytokines and delivered by APC
What is the role of signal 3 in T cell activation?
It dictates the differentiation of activated CD4 cells into different subseets of effector cells
What is the function of dendritic cells as an APC?
To present Ag and is crucial for the activation of naive T cells
What are the functions of macrophages and B cells?
They present Ag in order to receive help from effector T cells
What 2 types of dendritic cells exist?
Plasmacytoic (pDC, DC6) and myeloid (convential DC (DC2/3)
Explain the function of plasmacytoic dendritic cells
They are important in viral infection and secrete several type 1 alpha and beta interferons which express TLR 7 and 9 (these sense viral Ags)
Explain the function of myeloid dendritic cells
They are involved in the activatin of naive T cells.
- immature form found in epithelia and are macropinocytic (endocytose) & phagocytic
- they don’t express B7.1/2 until activated
- are induced to mature and migrate to lymph node following danger signal activation
Once activated where can mature DCs be found?
In T cell areas of lymphoid tissue
What happens to DC MHC class I and II molecules once activated?
They are loaded with peptides from pathogens they encountered in peripheral tissues
- their level of co stimulatory molecules will be very high so will express high levels of adhesion molecules
Why do some DCs (DC I) process exogenous Ag and present it via MHC I molecules?
It allows DC to activate CD8 T cells which can then kill other infected but non-APC cells that are expressing viral Ags on class I without co stimulatory molecules
Name key features of macropahges
- highly phagocytic
- express MHC II and B7 which increase T cell helpers
- reside in many tissues at peripheral sites, lymphoid tissues and others
- once activated secrete many inflammatory cytokines
B cells are good at phagocytosis. True or false?
False, they are very poor.
Explain the working mechanisms of B cells
They internalise soluble Ag for processing and presenting by BCR
- Ag binding to BCR upregulates B7 thus B cells are able to provide signal 2 required to activate T cells
What is Interlukin-2 (IL-2)
It’s a key cytokine for T cell survival and a potent autocrine T cell growth facyor
How does T cell affinity alter when the cell becomes activated?
Naive T cell expresses low affinity for IL2R but once activated this becomes high and IL-2 is secreted
What causes lots of T cell poliferation?
IL-2 bindng on activated T cells
What is the function of IL-2?
Allows rapid division of T celles, expands population of Ag specific activated T cells and is the target of immunosuppresive drugs
Following activation by APC T cells differentiation into which effector cells?
CD8+: cells acquire cytotoxic activity (kills cells expressing peptide/ MHC class I complexes)
CD4+: cells function by secreting cytokines, effecting on other cell types recognising peptide/ MHC class II complexes
What dictates the type of effector cell generated?
Signal 3 (cytokines) from APC + environment/ pathgen
How are CD8+ T cells activated?
Either directly by infected or cross presnting APC or may require additional help from CD4+ T cells
