t cell development and differentiation Flashcards
function of t cells
respond to bacterial antigens or vial antigens and mount an immune response to clear the bacteria or virus away from the body
- function in response to pathogens is shaped by an antigen, proinflam cytokines, inhibitory receptors and environmental stimuli
- these environmental stimuli include oxygen, amino acid, glucose and iron availability
how do t cells respond to soluble bacteria or viral antigens
they are triggered by peptides presented to them by mhc molecules on the surface of other cells
what cells express class 1 and class 2 mhc
most cells in the body express mhc class 1 molecules mhc class 2 molecules are present only on specialised cells - dendritic, activated macrophages and activated b cells
what is the key receptor that controls responses of t lymphocytes
the t cell antigen receptor (TCR)
TCR is a multisubunit complex expressed on the surface of membrane of all t cells
t cells can be divided into 2 major subpops based on the receptor they express
what are the 2 types of TCR in t cells
alpha/beta uses alpha/beta dimer to recognise antigen
gamma/delta uses gamma/delta dimer to recognise antigen
a/b is expressed by majority of recruiting t cells in blood and lymphatic system
y/d expressed by t cells lining the gut and skin
what are a/b t cells primarily responsible for
they recognise small peptides in complex with mhc class 1 or 2 and are primarily responsible for antigen specific cellular immunity
what are y/d t cells for
they are not mhc restricted and are involved in specific primary immune responses, particularly in young animals, tumour surveillance and have been implicated in wound healing
what are the ligands for y/d tcrs like
fundamentally different from short peptides that are seen by a/b t cells in the context of mch class 1 and 2 peptides they are not dependent on specialised antigen presenting cells for activation
what is the ligand for a/b tcrs
peptide/mhc complexes
t cells in the blood and lymphatics that express a/b tcrs can by subdivided into 2 groups based on the type of co-receptor they express (CD4 or CD8)
what are CD4 t cells
helper t cells
coreceptor for mhc class 2 molecules
triggered by peptide/mhc class 2 expressing cells
they produce cytokines and growth factors to regulate other immune cells
what are CD8 t cells
cytoxic t cells
coreceptor for mhc class 1
triggered by peptide/mhc class 1 expressing cells
differentiate to make cytoxic t cells that can kill infected cells
what is the normal ratio of cd4:cd8 t cells
2:1
how do t cells recognise a wide range of antigens
each t cell expresses a specific antigen receptor
this is due to the ab or yd subunits which are the receptor subunits that recognise peptide mhc complexes - these are highly variable
other antigen receptor subunits are invariant - CD3y/d/e/s
invariants dont recognise the antigen but are needed for signal transduction to transmit signals across the plasma membrane to the inside of the cell
ab and yd are very variable because the genes that encode them under go gene rearrangment which produces protein diversity
each t cell will express a unique antigen receptor
a/b subunits exist as a disulpohide linked heterodimer which recognises peptide/mhc complexes
stoichiometry of this complex is not yet understood
loss of any individual chain prevents the receptor assembling at the plasma membrane
TCR gene loci
random rearrangment of the exon is controlled by recominase genes rag 1 and 2
rearrangement occurs during t cell development forming TCR beta subunits - exons of the subunit are called V D J and C so the process it called VDJ rearrangement
during recombination double stranded breaks in dna occur that cut out exonsand dna repair enzymes rejoin the free ends
what does triggering TCR activate
tyrosine kinases Ick/fyn and ZAP70 which are coupled via signalling motifs (ITAMs) to the TCR
what do t cells do ?
respond to bacterial antigens or viral antigens and mount immune response
tcr triggering of niave t cells induces clonal proliferation and differentiation leading to affector t cell and their apoptosis producing memory t cells
activation has lots of receptors
how do t cells respond to stimulation
through a complex network of transcriptional and post-transcriptional mechanisms
- change migration pattern and move to the site of infection
- proliferate and clonally expand
- induce expression of genes for cytokines and cytokine receptors
- up regulate growth and protein synthesis to permit rapid cell division and cytokine production
- differentiate into killer cell or different types of helper t cells to make sure the immune response is appropriate
transcriptional reprogramming of t cells in response to immune stimulation
primary t cells express approx 14500 genes, 4 hrs of antigen exposure causes massive transcriptional reprogramming of the cells
TCR triggering down regulates and up regulates gene expression
what are the t cell receptor regulated genes
genes encoding cytokines
genes encoding cytokine receptors
genes encoding cell cycle regulators
genes encoding nutrient transporters - allows t cells to match metabolism to metabolic demand
genes encoding chemokine receptors and adhesion molecules - allows t cells to change the way they traffic around the body
how can antigen activated t cells differentiate to make different types of effector cells
specification of effector cells is controlled by signalling pathways induced by cytokines produced by activated t cells or cells of the innate immune system
type of cytokine made by innate lymphoid cells depends on the pathogen
t cell effector differentiation is initiated by the antigen receptor in a stop/go decision but the type of effector t cell produced is controlled by cytokine signalling
what are the type 1 cytokine receptors
il-2 - regulates t cell proliferation and differentiation of cytotoxic t cell and regulatory t cells
il-4 and il21 - crucial for th2 cell differentiation and hence b cell formation
il-7 crucial for survival and proliferation of t and b cell progenitors in the bone marrow and thymus
il-9 mast cell growth factor
il-15 - crucial for NK cell differentiation and t cell memory
yC cytokine receptor signal transduction using the il-2/il-7 receptor as an example
yC recruits the tyrosine kinase Jak3 into the cytokine receptor complex which is crucial for gene receptor to function
the gene encoding the yC is on an x xhormosome
what is x linked scid
males with mut on x chromosome which is located on the common gamma gene
non x linked scid
females or males with homozygous muts in jak3
