lymphocyte development Flashcards
what do t and b cells develop from
hematopoetic stem cells
where does lymphocyte specificty develop
in primary lymphoid otgans
how do b cells differentiate
from pluripotent hematopoetic stem cells (pHSC) in a series of distinct stages
during early embryonic development, pHSCs migrate into the fetal liver where they develop and mature into b cells in a transient wave - this preferentially populates the epithelia and lung as well as gut - associated lymphoid tissues
this is followed by continuous b cell development throughout life in the bone marrow to mature b cells that migrate to secondary lymphoid tissues where they mature
circulating antibody levels dont rise to protective levels until 6 months after birth
how do t cells develop a useful repertoire
TCR gene rearangments are completely random, during t cell development there is a selection of t cells with antigen receptors that can bind self mhc molecules
there is a strong selection against t cells tgat have high reactivity against self peptides as these will cause autoimmunity
t cells need to be able to recognise self mhc so they know they are normal
t cells develop in the thymus
when t cells are mature they express a t cell antigen and coreceptor that recognise mhc
what type of receptors do projenitors express
both cd4 and cd8 as they have not yet decided their lineage
how does t cell development work
pdk1 may control lineage commitment and loss of pdk1 may cause preferential development of g/d cells
majority of t cells in the periphery are mature a/b t cells
3% of the periphery are d/g t cells - it is thought that their development diverges from a/b development at the double negative stage
pdk1 may be the positive regulating a/b commitment and negative regulating y/d commitment
how is thymus development controlled by overlapping antigen receptors and cytokines
progenitors will express cKIT
cells need to make it to the next stage correctly to continue cell life
most cells will be doing rearrangements which will finish at around il-7 to preTCR stage
a chains are rearranged to match b chains
a lot of daughter cells are produced to ensure some survive to the end of cell rearrangement and progression
what are the stages of t cell development before the cell membrane stage
- rearrangement of 1 beta allele in the thymus
- occurs in t cell precursors that enter from bone marrow and dont express mhc receptors cd4 and cd8 - they are called double negative thymocytes
- cells that sucessfully rearrange a tcr beta allele will express functional receptor complex known as a pre tcr alpha and its signalling subunits of the cd3 antigen
- when pre tcr is expressed at the cell membrane it promotes cell survival and entry into the cell cycle
- hence all t cells in the periphery express the tcr beta allele of single specificity
what are the stages of t cell development at the cell membrane
- preTCR induces survival and differentiation to induce cells to up regulate CD4 and CD8
- pre tcr does not need a ligand to signal just expression at the cell membrane is required
- expression of all subunits is needed to stabilise the pre tcr at all times
how does beta selection work
preTCR cells express invariant signalling chains of a receptor know as the preTCR complex in their cytosol
CD3 y/d/e/f and one other invariant chain known as pre t alpha subunit
random b chain rearangements occur involving complex dna break/repair mechanism
the t cell thinks it has damaged dna and activates death pathwyas
if a productive beta chain is made it pairs with a pre T alpha and allows expression of a signalling complex (preTCR complex) at the plasma membrane
preTCR complex signals for further development
if the cell does not express a b chain it dies
when does alpha chain rearrangement occur
in double positive cells
positive and negative selection
t cells need to learn to recognise self mhc but not be autoreactive toward them
newly produced CD4/8 double positive thymocytes express preTCR complex - this is at the membrane inducing cell survival because its beta chain is dimerised to surrogate preT alpha subunit
if there is no successful TCR alpha expression by the time preTCR alpha is lost the cell will lose expresssion of TCR complexes and no longer recive survival signals
if the cell does express tcr alpha then it can pair with a beta chain and express a mauture a/b tcr complex at the membrane
this cant signal if its not triggered by a ligand - self peptides loaded onto the mhc molecules on the surface of thymic epithelial cells
how are useful t cells selected
t cells have to activates when self mhc are loaded with foreign peptides
we need to select t cells with some ability to recognise self mhc without selecting t cell that are strongly auto reactive
how do t cells see self peptides from peripheral organs in the thymus
thymic epithelial cells express tissue specific proteins normally found in terminally differentiated organs
what controls thymic expression of tissues antigens
AIRE - the gene that causes autoimmune polyendocrinopathy-candidas ectofermal dysplasia control the expression of tissue antigens in the thymus
no aire = no thymic expression of insulin - t cells reactive with insulin are not negatively selected, if they exit the thymus they will destroy the pancreas
