Cell-mediated immunity Flashcards
Why do we need cell-mediated immunity?
Designed to fight intracellular microbes
- bacteria in phagosomes (in phagocytes)
- viruses: in cellular cytoplasm
- parasites (helminths) - both intra- and extracellular
main mediators are T cells
Why are viruses largely intracellular organisms?
intracellular obligate pathogens
they require host cell machinery in order to survive and replicate
What are the main types of T cells?
Th1 (CD4+)
help phagocytes to kill ingested microbes
Th2 (CD4+)
help eosinophils/mast cells to kill helminths. (also active in IgE mediated allergy/anaphylaxis)
Th17 (CD4+)
role in defence against bacteria and fungi
CTL (CD8+)
kill cells infected by microbes that grow freely in the cytosol
How do T cells recognise antigens?
Only if digested and bound to MHC molecules on another cell (e.g. APC)
Cannot recognise Ag directly
What kind of Ag particles do T cell recognise?
CELL BOUND Ag
usually peptides via MHC
Which type of T cells recognise non-peptide antigens?
gamma- delta T cells
What kind of antigens do B cells recognise?
SOLUBLE or CELL BOUND Ag
Which MHC complexes are used in Ag presentation to T cells?
CD4+ T helper cells use MHC Class II (present on APCs)
CD8+ cytotoxic T cells use MHC class I (present on all nucleated cells)
What does Ag presentation via MHC to naive T cells cause?
Activation and production of their effector counterparts
What are the types of T cell receptor (TCR)?
alpha and beta TCR
this type of TCR present on CD4+ and CD8+ T cells
gamma/delta chains TCR present in gamma/delta T cells
What are the main structural elements of the alpha/beta T cell receptor (TCR)?
includes variable domains at Nter and constant domains towards Cter
TMEM domain is immediately upstream to Cter cytosolic (intracellular) portion
Variable regions contain hypervariable loops e.g. CDR3 (similar to Ig structure)
these regions are responsible for generating Ag specificity and binding between TCR
What is MHC restriction?
refers to type of antigen recognition in T cells
Concept that T cell will only respond to an Ag presented on a particular type of MHC molecule
e.g. CD4+ cells will only respond to Ag bound to MHC Class II molecules etc
What is the specific structure of the MHC I molecule?
alpha chain and beta 2 micro globulin chain
N.B. beta-2-microglobulin is smaller in size that the beta chain in MHC II
What is the specific structure of the MHC II molecule?
alpha chain and beta chain
Which T cells are not MHC-Ag restricted?
gamma-delta T cells
this means that it can respond to Ag bound to both MHC I and MHC II
Where are the different MHC molecules expressed?
MHC I = all nucleated cells
MHC II = APCs (mQ and DCs)
What is the generic structure of a MHC molecule?
2 peptide chains
form a groove between them that holds the Ag/peptide that is presented to T cell
What bonds hold the chains together in MHC molecules?
disulphide bonds
What regions determine the Ag binding specificity and diversity in TCR:MHC complex?
hypervariability loops
hypercomplimentarity domains
both present in TCR structure
What are dendritic cells?
type of APC
sentinel cells
present in skin, mucosa and tissues
role to capture microbes via phagocytosis
process pathogens and present Ag to T cells (via MHC class II for CD4+)
What is the main function of APCs?
capture and present Ag to T cells
provides link between innate and adaptive immune responses
What are the 3 signals needed for T cell activation via APCs?
Signal 1
MHC-peptide on APC
TCR on naive T cell
Signal 2
CD80/86 on APC
CD28 on naive T cell
regulatory signal of T cell activation
Signal 3
cytokines released from both APC and T cell
have both autocrine and paracrine effects
type of cytokine released will determine type of effector T cell produced
What is the extent of specificity for TCR?
Each TCR will recognise 1x MHC-Ag complex
Where does Ag presentation to T cells (from APCs) occur?
in the lymph nodes (usually
Where does the activated T cell go from the LN?
T cell effectors are ‘imprinted’ to travel back to the original site of where the microbe was encountered
They up regulate specific chemokine receptors that allow them to travel back to this site via chemotaxis
What controls MHC-peptide-TCR mediated activation of T cells ?
CD4 molecules on T helper cells
CD8 molecules on CTLs
Binding of these molecules at the MHC-peptide-TCR complex prevents premature activation that may lead to undue inflammation etc
How are Ag from EXTRACELLULAR pathogens processed for Ag presentation?
- phagocytosis into APCs
- processed in endolysosomes to make short peptides
- MHC II produced in ER, transported to endolysosomes
- peptide-MHC II complexes displayed on PM
- CD4+ helper T cells scan peptide:MHC II on APC PM
Why is nascent MHC molecule immediately bound by an invariant molecule in the ER?
When nothing is bound in the MHC groove, the chains have a tendency to dissociate from each other which can lead to their degradation in the cell
Invariant peptide (“li”) binds as a chaperone until the digested foreign Ag can bind at the endolysosome to prevent premature destruction of the nascent MHC molecule
How does the pathogenic Ag bind to the MHC if there is an invariant peptide bound?
invariant peptide is bound in a largely not specific manner
the pathogenic Ag has higher affinity for the MHC groove and therefore can displace the invariant peptide
How are Ag from INTRACELLULAR pathogens processed for Ag presentation?
e.g. virus
viral proteins produced/released in cytosol
- processed by proteasome into smaller peptides
- peptides transported to ER (retrograde) and loaded onto MHC I
- peptide-MHC I complexes are displayed on cell PM
- CD8+ CTLs scan peptide:MHC I complexes
How are MHC-peptide complexes moved to be inserted into the PM?
travel for ER via the Golgi
Secreted via exocytosis
TMEM domain at Cter of MHC allows insertion of complex into PM
Which T cells are capable of regulating the function of other T cells?
T regulatory cells (Tregs)
CD4+CD25+FOXP3+
How are Th1 and Th2 cells distinguished from each other?
mainly by the type of predominant cytokine that is produced
Th1 = IFN-g
Th2 = IL-4, IL-5, IL-13
What is a Th1 immune response?
main cytokine: IFN-g
functions to activate macrophages -> increase intracellular pathogen destruction
They also stimulation production of IgG Ab -> increased microbe phagocytosis
Which diseases are caused by Th1-mediated immune pathology?
granulomas
autoimmunity
What are the main steps in pathogen killing in phagocytes?
- engulfment of microbes by phagocytosis
- endolysosomal degradation of microbes to generate smaller peptides
- pathogen destruction: oxygen-dependent and independent mechanisms
Which microbes are known to be able to block destruction by phagocytosis?
salmonella: resistant to ROS
mycobacterium: blocks phagosome-lysosome fusion
What happens to microbes that cannot be killed by macrophages?
thye persist in phagosomes
solution: need Th1 cells to help kill these microbes
Which signals from Th1 cells are needed to mediate macrophage activation?
- Contact mediated: CD40-CD40L
- Soluble: IFN-g
How do the contact-mediated signals between Th1 cells and macrophages ensure that activation is restricted to the infected macrophage only?
CD40 (on mQ)-CD40L (on Th1)
specific to that one infected macrophage
therefore don’t have collateral activation of surrounding (healthy) macrophages
What does Th1-mediated macrophage activation lead to?
increase in ROS, NO
increase in lysosomal enzyme -> killing of phagocytosed microbes
inflammatory cytokines: IFN-g, IL-1, IL-12 (neutrophil, monocyte recruitment and phagocytosis)
tissue repair
What mediators are involved in tissue repair in Th1 immune responses?
PDGF: fibroblast proliferation
TGF-beta: collagen synthesis
FGF: angiogenesis
culminate in tissue repair
When are Th2 mediated immune responses indicated?
respond against helminth infection
= too large to be phagocytosed by neutrophils and macrophages and thick coat is resistant to microbicidal activities of mQ
Th2 cells help B cells to produce Ab OPSONISATION
These Ab then activate eosinophils/mast cells DEGRANULATION and pathogen destruction
What are the Th2 mediated immune responses
Th2 cytokines: IL-4, IL-5, IL-13
IL-4, IL-13 stimulates IgE production, which then opsonises helminths
Eosinophils bind IgE via FceIII receptors
IL-5 activate bound eosinophils to kill helminths
Degranulation: release of MBP, MCP extracellularly to destroy worms
How does mast cell degranulation in Th2 responses mediate local inflammation?
mast cell degranulation
- > release of vasoactive amines (histamine), TNFa, lipid mediators (leukotrienes)
- > local inflammation -> helps to destroy parasite
How do mast cells and eosinophils target worm/helminth?
Fc portion of IgE: recognised by specific PM receptors on mast cells/eosinophils
IgE binds helminth (OPSONISATION)
IgE also important for recruitment of these cells
Binding of IgE: degranulation
How may an inappropriate Th1 response in a helminth infection cause damage?
may cause autoimmunity or hypersensitivity pathology
Th1 is too strong of an infection on host cells and therefore can cause host damage
How may an inappropriate Th2 response in a bacterial infection cause damage?
may cause disseminated infection
Th2 not as strong of an immune insult as Th1
What are the CD8+ CTL mediated immune response?
function to eliminate intracellular microbes (in cytosol) targets mainly viruses and microbes that escape from phagosomes
CTLs important in immunity to tumour and rejection in transplantation
How is killing mediated in CD8+ CTLs?
killing is Ag-specific and contact-dependent
unaffected/healthy cells are not killed by CTLs
CTLs deliver a lethal hit and then detach (allowing target to die)
mediated by cytolytic proteins stored in SGs
What are the cytolytic proteins stored in CTL SGs?
Perforin: forms pores and facilitates granzyme delivery
Granzymes (A, B, C): initiate apoptosis
How do CTLs ensure that neighbouring healthy cells are not killed?
cytolytic proteins are delivered at the contact site between CTL and target cell
SGs released via exocytosis
How do CTL-cytolytic cells mediate apoptosis?
granzymes activate caspases
Granzyme B triggers mitochrondrial apoptotic pathway
What is an additional mechanism of killing cells by CTLs?
FasL (on CTL) binds Fas receptor (on target cell)
activates caspases and apoptosis
What is the ultimate function of killing infected cells by CTLs?
elimination of infection reservoir in body/host
