Lymphocyte differentiation in central lymphoid organs Flashcards
where do lymphocytes originate from
pluripotent hematopoietic stem cells of bone marrow
what happens to the lympocytes that differentiate in bone marrow, and those that go to thymus
B cells
T cells
what kind of lymphoid organs are Bone marrow nd thymus
central/primary
what is antigen independant differentiation
immature lymphocytes build their receptors for antigen (become immunocompetent)
what kind of genes do germline DNA NOT contain
- doesn’t contain ready made genes for variable parts of Igs + TCR chains
- has numerous tandemly arranged gene fragments. the random combos produces the genes for variable parts
What is VDJ recombination
cutting and joining together DNA fragments
WHat is the light Ig chain and TCR chain made from
what is the heavy chain and TCR β chain made from
- 2 fragments: V + J (respectively)
- 3 fragments: V, D + J (respectively)
How is additional diversity created
enxyme: terminal deoxynucleotidyl transferase (Tdt)
inserts single random nucleotides btw fragments
Red bone marrow + location
main hematopoietic organ (except in embryo + foetus)
Located in spongy bones, filling spaces btw bone trabeculae
what is the stroma of the bone marrow
(connective tissue from mesynchymal cells)
- provides microenvironment for blood cell differentiation
- formed by stromal/ reticular cells cos the fibres prod by them form 3D network
what do hematopoietic stem cells give rise to
lymphoid stem cell / common lymphoid progenitor
some lymphoid stem cells become pro B cells which poliferate and differnetiate. what the most imp elemt of B cell differentiation
become immunocompetent (building antigen receptor)
Pro B cells will rearrange heavy chain genes - D J then VDJ. What is allelic exclusion
if first rearrangement successful,
the cell will use only the rearranged chromosome and will not touch its homologue.
why does first rearrangement become unsuccessful. what happens after
- if frameshift / early stop codon obtained
- cell then tries to rearrange 2nd chromosome, if fail again then it will commit apoptosis
what happens to successful pro B cells
They synthesize class mu heavy chain. It remains in the
cytoplasm
What do Pre B cells rearrange
what happens with failure
VJ of light chain gens starting with Kappa. success leads to allelic exclusion.
- failure: homologous chromosome rearranged.
- if both kappa attempts fail, lambda genes tried
what happens when cells acquires light chain
it expresses IgM receptor on its surface and becomes
an immature B cell. It is immunocompetent.
Immature B cells are checked for eventual
reaction of their IgM receptor with a normal
tissue component called what
autoantigen
B lymphocytes that react with autoantigens are called what
self reactive / autoreactive
what do autoreactive cells do. what is the proccess called
Receptor editing - the cells receive a signal to correct
themselves. They reactivate their V(D)J
recombination machinery and attempt to
produce other, better antibody chains.
what happens when B cell gets good Ig receptor
allowed to leave the bone marrow for the
periphery.
what happens to B cells that fail in getting Ig receptor
undergo apoptosis = negative selection (ridding self reactive lymphocytes)
where is the thymus located
cranially from the heart and behind the
sternum. It is composed of two identical lobes.
what is the tthymus divided into
cortex (subcapsule) +medulla.
Border btw them is = cortico-medullary junction.
how do the t lymphocytes develop in thymus
same as B
proliferation, differentiation, apoptosis
cells in the stroma of thymus
hematopoietic (thymocytes) + stromal cells
provides microenvironment for differentiation
what are the 2 tyoes of stromal cells and their location
- thymic epithelial cells (cortex + medulla)
- dendritic cells + macrophages (medulla)
They can be antigen presenting cells
structure of dendritic cells
. branch-like projections,
. related to mononuclear phagocytes
. originate from bone marrow.
are the stromal cells antigen presetign
yes
they express MHC class 1 + 2
thymocyte path
. travel in bloodstream
. enters thymus via cortico- medullary junction
. then migrates to outer cortex
. then moves to medulla to mature
what receptor do lymphoid progenitors express
Notch receptor
some stromal cells express notch ligand which allows progenitor to become T cell
wha happens when Notch receptor not present / over reactive. conclusion?
- no T cells made , B cells will differentiate in thymus
- no B cells, abnormal T cells in bone marrow
** shows that lymphoid progenitors become B cells by
default and need a Notch signal to become
T cells.
why are thymocytes called double negative
they express neither CD4 nor CD8
Where do thymocytes proliferate. how do they develop
- proliferates while migrating to outer cortex
- They express Tdt and start V(D)J recombination
to produce TCR.
**same as B cells, success in
rearrangement leads to allelic exclusion, 1
unsuccessful attempt prompts rearrangment on
homologous chromosome, and double failure
triggers apoptosis.
where are β chain genes are rearranged.
outer cortex
thymocyte migrates back to cortico medullary junction + rearranges α chain genes.
What happens to thymocytes after successful VDJ recombination
- inner cortex thymocytes express TCR2 and CD3 on
their surface - They also express both CD4 and CD8 and
therefore are called double positive
What is positive selection in thymocytes
- TCR must prove its functionality by
recognizing MHC presented by cortical thymic epithelial cells. - Thymocytes that fail to bind MHC + peptide die
by apoptosis. Only those that bind MHC survive.
why does B cells not hv positive selection
step is absent in B cells because they have
no MHC restriction (B cell receptors do not check
if the antigen was presented by MHC).
why do thymocytes hv to be double positive. what does positive selection test
- because they cannot “know” beforehand which class of MHC is better recognized by their TCR.
- Positive selection tests the reaction of TCR
with both MHC-I and MHC-II. So, the
thymocyte preference for class I or II MHC
becomes known.
how are thymocytes single positive
Thymocytes recognizing MHC-I + peptide
will not need CD4 and stop expressing it.
Those recognizing MHC-II + peptide stop
expressing CD8.
to be useful where do t cells bind to
how can restricion for self MHC be tested
- foreign peptide on self MHC
- tested only on MHC + self peptide, because only self antigens are available in the thymus.
what is negative selection in thymosytes
function is to eliminate self-reactive T cells which are very dangerous. ( those best during positive selection must die now)
- what does negative selection involve?
TCRs that bind self peptide + MHC
moderately, will bind toforeign peptide + MHC
strongly.
dendritic cells present self peptides +
MHC to thymocytes + induce apoptosis in those that
react strongly.
what does T helper 17 cells do
pro inflammatory - prod interlukin 17
defense against extracellular pathogens, particularly at the mucosal and epithelial barriers,
abnormal activation can lead to autoimmune diseases
what do regulatory T cells do
maintain tolerance to self- antigens, and prevent autoimmune disease.
do thymocytes hv receptor editing and what happens next in their development after bypassing apoptois
no
single positive medullary thymocytes
that survive leave the thymus as
immunocompetent, mature T cells.
- They go to peripheral lymphoid tissues to
take part in immune response.
qhat happens to thymus after fast prenatal growth
thymus involutes ( reduce in mass)
can do this as t cells hv very long life spans
in early childhood the peripheral
lymphoid organs are populated by
mature incompetent T cells that persist
in later years. what do this. what does this mean for later life
Guarantees efficient immune
response even without new reinforcements from the thymus.
- Removal of thymus (thymectomy) has
little effect in adults.
In healthy organisms even the
involuted thymus has active parts so
produces new T cells till advanced age.
