lecture 5 Flashcards
what is the method of T cell mediated immunity?
- naive T cells (that have survived +ve and -ve selection) leave the thymus
- recirculate via blood/lymphatics through secondary lymphoid tissue
what do naive T cells express?
either CD4 or CD8
how do naive T cells become effector/memory T cells?
when encounter an antigen
what does contact with a specific antigen and APC lead to?
clonal proliferation and differentiation
what do cd8 T cells do?
kill infected cells
cytotoxic effect
what do cd4 T cells do?
secrete cytokines
helper effector T cells
what happens in the lymphoid tissue?
- T cells recognise Ag/MHC on APCs
- array of APC found, trap and present Ag (in lymph nodes or spleen where T cells go once leave thymus)
what happens following activation of T cells?
- T cell effects leave the areas and migrate to the sites of infection
-deals with the start site of pathogen entry
how do naive T cells get where they need to be?
- enter lymph node from blood via high endothelial venules (HEV)
- move into T cell area that is rich in dendritic cells and macrophages (APC)
- APC present antigen and deliver other activation signals (cytokines)
what are high endothelial venules?
distinct compartments in lymph nodes
what happens to T cells that aren’t activated?
- leave lymph node via cortical sinuses into lymphatics
-reenter circulation
-recycled for another day
-short life span so die if cant eventually find an antigen
what happens when the T cells is activated?
-proliferation and activation of cells
-actively blocked from leaving that environment, have to expand there
-once expanded to certain level, they leave back to site where antigen is encountered and can deal with antigen
what are cell adhesion molecules (CAM)?
-mediate cell interactions
-molecules expressed on surface of T cells (chemokine receptors), binds ligand s (chemokines) expressed or released by other cells
-synthesised by lots of cells
-acts as sign posts fort cells to follow to work out where to go
what occurs with CAMs in close association to other cells?
-mediate cell/cell interactions
-hold cells on the APC so assess whether peptide Mac is capable of recepting
what are the different ways CAMs interact?
-naive T cell with HEV
-T cell with APC
-effector T cell and target cell
what happens with T cell contact with APC?
- T cells contact APC using CAMs
- TCR scans APC peptide/ MHC complexes
what happens if TCR doesn’t recognise the APC/MHC complex?
disengages
what happens if TCR recognises the APC/MHC complex?
signal released
how is the signal released?
-TCR gets signal through CD3 signalling complex
-causes T cell mediated response
what are occurs after cell contact with APC?
-increases affinity of CAM interactions
-T cell divides
-progeny differentiate to effector cells to produce T cell mediated responses
what 2 molecules are important in cell interactions?
LFA-1 and ICAM-1
what is the function of LFA-1 and ICAM-1?
- LFA-1 and ICAM-1 allow cellist stick together while decision is made about accepting
- CD4 holds cells together and interacts with class 2
- interaction takes place driving signal to alter this
- LFA-1 binds to ICAM-1 as a result of initial interactions - allows the two cells to be locked together and allow signalling to occur if correct peptide that TCR recognises
how does co-stimulation of signal 1 occur?
- T cell receive signal through its CD3 complex
-if TCR is recognising the peptide MHC complex -signal 1
how is signal 2 initiated?
-APC express co-stimulatory molecules (B7.1/B7.2 or CD80/CD86) that bind CD28 expressed by naive T cells and delivers signal 2 to the T cell
how is signal 3 delivered?
APCs release cytokines which bind cytokine receptors now unregulated on naive T cells which deliver signal 3
what are co-stimulatory molecules expressed on?
APCs only
what occurs once activated by the three signals?
-activated T cells now proliferate and express ICOS and CTLA-4
-need inbuilt way of turning off the activated T cells
what is the function of ICOS?
binds ICOSL onAPC to induce cytokine secretion by T cells
related to CD28
what is the function of CTLA-4?
shows stronger binding to B7.1/B7.2 than CD28
acts as an antagonist
highly related to CD28
what does the binding of CTLA-4 to B7.1/2 on APC do?
delivers a negative signal to the activated T cell
dampens down/limits the T cell response
what does a mutation in CTLA-4 cause?
-over-responsive immune system
-leads to autoimmune disease as T cell responses turned off
how are the affects of the mutation reversed?
-the signals are blocked with antibodies
-makes T cells more responsive
-encourages body to overreact and keep responding to something
-stops immune response being turned off by tumours
what do these mutations cause?
-type 1 diabetes
what are the types of co-stimulatory molecules?
B7.1 (CD80) and B7.2 (CD86)
how does the expression of co-stimulatory molecules vary?
-constitutive on mature dendritic cells
-inducible on macrophages and B cells
what does activation of APC by pathogens induce?
co-stimulation expression so APC can provide signal 2 to activate T cells
what is the danger signal?
-binding pathogen associated molecules activates the APC
-APC need to present something to T cells but also perceive danger
-ensures signal 2 to activate T cell mediated response only occurs during infection
what is the response to the danger signal?
-ability to up regulate co-stimulatory molecules as a consequence of pattern recognition receptor engagement
what is the purpose of signal 3?
decides what type of T cell/effector is going to be made
what is the loop that occurs in signal 3?
the cytokine released from APC that stimulates the T cell to differentiate is also produced by that T cell- perpetuate themselves
what T cell does IL-4 produce?
Th2 cells (t helper 2 cells)- mediate activation and maintain immune response
what T cell does IL-12 and IFN-gamma produce?
Th1 cells
what T cell does TGF-beta and IL-6 produce?
Th17 cells - mediate defensive mechanisms
what T cell does IL-6 create?
Tfh cells - T follicular helper cells - development
what does TGF-beta form?
T reg cells - control clonal expansion etc.
what do APCs express?
MHC class 11 molecules
what are the types of APCs?
-dendritic cells
-macrophages and B cells
what is function of dendritic cells?
-to present antigens
-crucial for activation of naive T cells
what is the function of macrophages and B cells?
-present antigen in order receive help from effector T cells
what are the types of dendritic cell?
- myeloid (conventional DC2,3) - potent APC, activation of naive T cells
- plasmacytoid (pDC, DC6)- important in viral infection, secrete several type 1 alpha and beta interferons, express TLR 7 and 9 (sense viral antigens)
what is the function of myeloid dendritic cells?
-initiate T cell responses
-bone marrow derived
-immature form found in epithelia
-engulfs by phagocytosis
-doesn’t express co-stimulatory molecules until activated
-migrate to lymph node following danger signal activation
-sense danger as have pattern recognition receptors
-upregulate B7 if sense danger
what occurs after activation of DC?
-mature DC (2,3) found in T cell areas of lymphoid tissues
-DC MHC class 1 and 2 will be loaded with peptides from pathogens they encountered in peripheral tissues
-levels of co-stimulatory molecules very high
-express high levels of adhesion molecules - efficient activators of naive T cells
what is the process after activation?
- immature dendritic cells in peripheral tissues encounter pathogens and are activated by PAMPs
- DC eats bacteria, chops up and puts on surface in association with class 2
- move towards lymph nodes
- cells go to site where needed most
- b7 molecules on surface
- DC releases cytokines to produce signal 3
what is cross presentation?
some specialised DC (DC 1) take up proteins from outside and instead of presenting on class 2, they present on class 1
what is the benefit of cross presentation?
-allows DC to activate naive CD8 T cells
-then these CD8 effector cells can kill infected cells that aren’t APC so not expressing co-stim
what are the features of macrophages?
-function as scavengers/killers of pathogens
-highly phagocytic
-express MHC class 2 and B7 which increases following T cell help
resident in many tissues at peripheral sites
-once activated by T cells, secrete many inflammatory cytokines
what are the features of B cells?
-poor at phagocytosis
-internalise soluble antigens for processing and presentation by BCR-upregulates co-stim on B cells so they become APCs that deliver signal 2 and express class 2 scan deliver signal 1 t to cells and also signal 2 and 3
-found in lymph node presenting to T cells
how do B cells act as antigen specific APCs?
-only antigen specific B cell binds the antigen
-specific antigen efficiently internalised by receptor mediated endocytosis
-high density of specific antigen fragments presented
what is a key cytokine in T cell survival ?
IL-2 (interleukin-2)
what is the function of IL-2?
-essential for T cell activation
-cytokine that T cells make themselves to cause them to proliferate
-potent autocrine T cell growth factor
how does high affinity for IL2 cause proliferation?
-naive T cells express low affinity of IL2
-once T cells activated they express high affinity IL-2 receptors and secrete IL-2
-IL-2 binding to IL-2R on activated T cells = lots of T cell proliferation
what is the function of IL-2?
-allows rapid division of T cells
-expands population of antigen specific activated T cells - happens downstream of signals
-need to make lots of copies with unique receptor deed to bind to specific peptide
-lots of levels of control are in place
-target of immunosuppressive drugs eg. cyclosporin
once activated, what do T cells differentiate into?
effector T cells
-CD8 cells acquire cytotoxic activity (kills cells expressing peptide/MHC class 1 complexes)
-CD4 cells function by secreting cytokines, recognise peptide/MHC class 11 complexes
what do effector T cells do?
-display effector function when TCR engaged - no longer require stimulation, change expression of adhesion molecules
-no longer enter lymph nodes but enter tissues via activated endothelia at sites of infection and inflammation - migrate nowhere needed
how are CD8+ T cells activated?
-requires high levels of co-stimulator activity
-can be activated directly by infected or cross presenting APC or may require additional help from CD4+ T cells
