lymphocyte development Flashcards
(35 cards)
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
how are t cells selected
random gene rearrangement produces thymocytes that express an a/b TCR
if a thymocyte ends up with a tcr with no reactivity with self peptide/ mhc complexes then this tcr can not give survival signals and it will die
if the cell is weakly reactive with self peptide/mhc it generates survival signals - this is positive selection
if the tcr is strongly reactive with self peptide/mhc it induces apoptosis - this is negative selection
positively selected cells exit to the periphery
how are b cells lymphocytes that are central to humoral response
b cells detect and respond to antigen via antigen specific BCR
- in response to antigens b cells will clonally proliferate
- differentiate into diff effector antibody producing cells
- secrete protective antigen specific antobodies
generation of a population of mature b cells capable of responding to antigens is dependent on a coordinated development programme in the bone marrow
- failure or defects in this developmental process can be catastrophic
phase 1 of b cell development
precursor b cells acquire functional antigen receptors through Ig gene rearrangements
although each mature b cell expresses ig of just one anitigen specificity the b cell population as a whole represents a vast repertoire of igs with differnet binding specificities
generation of diverse and clonally expressed b cell receptors in the bone marrow = repertoire assembly
phase 2 of b cell development
negative selection takes place to prevent development of b cell mediated autoimmune disease
begins in the bone marrow and travels to secondary lymphoid tissue
alteration, elimination or inactivation of bcrs that bind to self antigens = neg selection
phase 3 of b cell development
during positive selection, immature b cells compete for a limited no of sites in secondary lymphoid tissue where their final maturation step takes place
promotion of a fraction of immature cells to become mature b cells = positive selection
b cell development occurs through several key stanges
rearrangement and expression of immunogloublin genes
developing b cells are programmed to die by apoptosis unless they are rescued by survival signals from productively assembled pre bcr and mature bcr complexes
b cells only survive if they sucessfully complete V(D)J rearrangement to produce functional Ig mu/ delta and Ig kappa/lambda proteins
production rate is enormous in healthy adults
only 5% of b cells mature to functional b cells daily - other 95% undergo apoptosis
this process continues throughout life but numbers decline with age
how do cytokines control commitment to haematopoietuc stem cells to b cell lineage
hscs localise to specific niches that allow for their long therm survival in bone marrow
stromal cells promote development of b cells from hcs
1. adhesion molecules help form contacts between stromal cells and developing b cells
2. soluble and membrane bound cytokines and chemokines control lymphocyte proliferation and differentiation
IL-7 and IL-7 receptor deficient mice are severely deficient in b cell development
in humans, b cells can develop without IL-7 suggesting thymic stromal lymphoprotein or another unknown cytokine can substitute this role
IL-7 is required for human t cell development
SCF in b cell lineage
SCF is a membrane bound cytokine expressed on the bone marrow stromal cells that stimulates growth of hscs and earliest b cell projenitors - SCF interacts with receptor cKIT
Flt3 ligand in b cell lineage
fms like tyrosine kinase ligand of FLT3-L
