T cells develop in the
thymus
Mature T cells leave the thymus and travel to the
secondary lymphoid tissues
The cortex of the thymus consits of
immature thymocytes
branched cortical epithelial cells
few macrophages
The medulla consists of
mature thymocytes
medullary epethelial cells
dendritic cells
macrophages
The human thymus is fully developed before birth and as a person ages
the thymus begins to
degenerate and replaced with fatty tissue
When entering the thymus T cells are
CD 34+
This cells begin to differentiate and lose their stem cells
markers after about a week
Commitment to the T cell lineage involves changes in
gene expression and in cell surface markers
The above cells are called
double negative thymocytes
DO NOT EXPRESS CD4, or CD8
IL7 is the
first cytokine important in T cell development
Notch-1 is a major regulator of
T cell development is driven by Notch-1
helps in transcription of gene necessary for T cell development
The two lineages of T cells arise from a common
thymocyte progenitor
?:? and g:? T cells develop from a common
double negetive T cell progenitor
Proliferation of these common progenitors followed by rearragement of
the of the ?-, g-, and ?-chain genes leads to
early commitment of some cells to the g:? T-cell lineage, whereas
others rearrange the ?-chain gene first and temporarily halt gene
rearrangement at this point
A productive alpha chain gene rearrangements in these cells produce
double positive CD4,CD8 alpha:beta cells
A minority of double positive thymocytes give rise to
g:?
This ends the early stage of alpha:beta T cell development
The two kinds of T cells develop from
a common double negative T cell progenitor
Gene rearrangement in double- negative thymocytes leads to assembly
of either
?:? receptor
pre T cell receptor
Beta and delta chains are like
immunoglobulin heavy chain and contain VDJ segments
alpha and gamma are like
immunoglobulin light chain and contain VJ segments
For beta and delta
First rearrangement joins the DJ
Second rearrangement joins the V to the DJ
For alpha and gamma a single rearrangment joins
V to J
The alpha chain gene rearrangement occurs
last
Alpha chain (like light chain) has a surrogate pTalpha to test
the productive beta chain protein in the endoplasmic reticulum
If the beta chain binds to pTalpha this heterodimer assembles
with the CD3 complex
This assembly is now called the Pre T cell receptor
A pre t cell receptor is assembled by successfull beta chain gene
rerrangement is made before the others
which signals the cell to proliferate, express CD4, CD8, and become a
pre t cell
Comparison of the structures of the pre t cell receptor and T cell
receptor is
that the alpha chain of the T cell receptor is replaced by the
pTalpha chain in the pre T cell receptor
Thymocytes can make four attempts to
rearrange a beta chain gene
80% success rate producing a beta chain gene rearrangement
Rearrangement of the alpha chain gene occurs only in the
pre t cells
no pre t cell no rearrangement of the alpha chain gene
First DC4, CD8 are made
double positive cells
Th-POK
needed for development of single-positive CD4 T helper cells
Once a developing thymocyte expresses an alpha:beta receptor and CD4
and CD8 on its surface, it undergoes two types of selection
positive and negative selection
Both types of selection involve
testing the receptors interactions with the complexes of self
peptides bound by self-MHC molecules on the surface of thymic cells
T cells that recognize self-MHC molecules are
positively selected in the thymus (cortex)
Positive selection is the job for
epithelial cells in the cortex of the thymus .
Positive selection is the process whereby a small subpopulation is
selected and signaled to mature further
Mechanism of positive selection
T cells with T cell receptor that binds to self-MHC class I
molecule on thymic cortical epithelial cells and macrophages are
signaled to
survive and proceed to negative selection
T cells with a t cell receptor that binds to no self MHC class i
molecules are signaled to
die by apoptosis
Continuing alpha chain gene rearrangement increases the
chance for positive selection
if the first alpha chain gene rearrangment that a pre T cell makes
is productive and leads to the assembly of an alpha:beta receptor that
interacts with a self MHC molecule positive selection will proceed
The t cell is then signaled to turn off the RAG genes and
recombination machinery
cell enters proliferation
If the T cell receptor does not bind to self-MHC molecule
rearrangment of the alpha chain continues until 3 to 4 days to improve
its chances of having a binding site that bind MHC molecules
there is no allelic exclusion in the alpha chain rearrangement
unlike the beta chain
Positive selection determines expression of either
CD4 or the CD8 co-receptor
Double positive becomes a
single positive thymocyte
T cells specific for self antigens are removed in the thymus by
negative selection
Negative selection deletes by apoptosis T cells whose antigen receptors
bind too strongly to the complexes of self peptides and self MHC
molecules presented by cells in the thymus
Such cells are autoreactive if allowed to enter the peripheral
circulation the could cause damage and autoimmunue dieases
Negative selection is mediated by
dendritic, macrophages including thymocytes themselves
autoreactive T cells are suppressed by CD4 T regulatory cells
T reg are specific for self antigens
T reg cells have CD25 on its surface
Having survived both positive and negative selection
NOW the mature single positive T cells ( aka naive t cell) leave the
thymus in the blood and circulate thru secondary lymphoid organs
Once activated by antigen they differenciate into
effector T cell