Chapter 7 Flashcards
Double neg thymocytes initiate rearrangement at the
B, gamma , gamma loci before all other T cell receptor genes
Function of neg selec in the thymus is to elimate
Autoreactive thymocytes
If TCR on a double pos thymocyte binds to a self peptide : self MHC I complex with LOW AFFINiTY
Results in pos selec of CD8 TC
In adults the mature TC repertoire is self renewing and does not require a thymus for provision of new TC
Correct
AIRE def
Exhibit APECED
TC analog of VpreB: lambada 5
Protein preTa (pTa)
Pta
Also binds like imm heavy chain binds to CD3 an zeta - assemble indices TC prolif and rearrangement of TCR beta leading to allelic exclusion
TC k pt
- Occurs after the rearrangement of the beta chain locus which test the ability of the beta chain to ass with pta, the surrogate light chain, and for the Pre -TCR on the surface
- After rearrangement of alpha chain locus test the ability of the alpha chain to associate with the b chain and for the TCR on the surface
MHC II expression
APC cells
To produce an antibody
Require TC in the form of cytokines produced by CD4 TH2 cells
Role of regulatory CD4 cell
T reg
They suppress the proliferation of naive auto-reactive CD4 TC by secreting inhibitory cytokines.
Require both Treg and the other CD4 are interacting with the same APC
TC are derived from
BM stem cells
Lymphoid progenitor cells in the
Thymus- initiation of TC devel
Things we have to select for in TCD
Host MHC
CD4 or CD8
Overview of TC devl
Thymus unit of TCD TCR speciality -VDJ recom MHC restriction-pos selec Selection of -TH or cytoxic Elimination of self spec TC-neg sele
TC linage
A:b
G:d
Thymus contain what precursor
Contains thymocytes =precursors
Thymus organization
Cortex = immature thymocytes
-enter by HEV then start in cortex
Medulla= mature thymocytes
-selection occurs, mature TC
No thymus means what cells
No T cells but yes BC but they would not function bcuz BC need helper TC
No thymus what syndrome
DiGeoegr
No thymus dev
Normal BC
Symptoms of SCID
Removal of thymus
A thymectomy
-only in adults
Auto imm
TC lineage
Interaction bw stromal cells
Signaled to divide
Committed
Double neg- bcuz they do not have CD4 or CD8
What regulates TCD
IL-7
Notch 1
What is IL-7
Binds to receptor on cd34
Import for reg of TCD
Notch 1
Import for reg of TCD
Cell surface red on thymocytes
Bind to thymic epith
Drive TC differentiation
Analogous to Pax-5
TC lineage
Rearrangement now at gamma , delta, beta loci occur at the same time
G:D compete with B
If rearrangement at g:d then what type of cell?
G:d TC
If b develop from rearrangement then what kind of cell?
Dev to Pre TCR
No commitment yet
Now that we have b chain production why happens?
Gene rearrangement stops
Cd4 cd8 receptors are formed
Now it is a double positive thymocytes
After B rearrangement now what occurs after becoming a double thymocytes ?
Now rearrangement of alpha chain
Rearrangement of g:d continue
What does a uncommitted progenitor cell express?
CD34 - stem cell surface marker and
CD44 -adhesion
What does a double neg thymocyte committed to the TC lineage express?
CD2
CD5
IL-7
CD1A- MHC class one molecule
What does double neg thymocyte Not have?
CD34
CD44
Because after a week the cells have lost these markers and have become thymocytes
CD4
CD8
CD2 and CD5 do what?
Present on a double neg thymocytes remember that after becoming a thymocyte they are committed to the TC lineage so the. They express CD2- an adhesion molecule and CD5
CD 34 is on what type of cell?
Uncommitted progenitor
What type of cell is CD2 expressed on?
Committed double neg TC progenitor
What happens after cd2 expressed in double neg TC progen?
Cell can determine pathway by sequence in which TCr genes make productive rearrangement
So could be g:d or a:b
If g:d is made before B what happens?
G:d is a heterodimer
assembly of CD3
Signals stop of B chain rearrangement
Then g:d leaves thymus and enter circulation
If B chain is produced then what?
B chain moves to ER
Test ability to bind of invariant alpha chain pta
If b chain binds then this heterodimer assembles with the CD3 and zeta chain to for PRe-TCR
The invariant alpha chain pta is analogous to what in the BC
VpreB and lambada 5
If a b chain gene rearrangement is made then what will be made next?
A Pre-TCR is assembled if B chain binds to pta
Then Pre-TCR signals the cell to proliferate expressing cd4 & cd8 and become Pre TC
Thymocytes can make how many attempts to rearrange the beta chain?
Four attempts
Two times on each Cb genes
Also more infor on B chain
Once b chain is made then there will be suppression of what?
RAG 1 and 2 because this ensures that only one B chain gene has a productive rearrangement and expressed
RAG 1 and 2 suppression this ensures that only one B chain gene has a productive rearrangement and expressed what is this called??
Allelic exclusion
Where are doub pos thymocytes found?
Inner cortex Of thymus
What are the TCR a chains comparable to in the Ig?
Kappa and lambada light chains
They do not have D segments
Are rearranged only after their partner chain receptor has been expressed
A chains have what gene segments?
V-J
A chain be arranged how many times?
The alpha chain can has as many rearrangements until either:
a productive rearrangement occurs
Or the supply of VJ gene segments is exhausted -whereupon the cell dies
Why when rearranging the alpha chain does it exclude delta?
The delta chain is in the middle and is cut out
What is really the summary of TCD?
Uncommitted progen expresses CD34
Then CD2 is expressed now committed doub neg TC progenitor
Then makes a decision as to what direction the cell will go
If B chain is made first (4attempts) then Pre-TC stops gene rearrangement an sends signals o get CD4 CD8 and now becomes a double pos thymocytes still uncommitted at this point.
Rag 1&2 halted allelic exclusion
Now Pre-TC turns back on the recombination to arrange a g d
Now a chain is being made
But b chain moves to ER and binds to an invariant alpha chain pTa
Then once successful a chain it translocates to ER and test for ability to bind B chain
If it binds then it survives
If not then further alpha chain gene rearrangement
Why is the pta made?
So that the new b chain can quickly become the Pre-TC
What does the RAG 1&2 do?
Essential for gene rearrangement and are selectively expressed
What enzyme is in involved for somatic recomb?
TdT- inserts N nucleotides and are expressed thought the TCD phase
What signals does the Pre TC depend on?
CD4/8- co receptors
CD3- the signaling complex
ZAP-70- involved in relaying signals from the co-receptors
CD2- adhesion molecule on TC the interact with CD58
CD58- cell surface protein generates signals
GATA-3: expressed in early TC progenitors and are essential for TCD
What is Th-POK?
Expressed in late in development and is required for development of
Single pos CD4 from the doub pos thymocytes
What are the two types of screening that the a:b double positive thymocyte undergoes?
Positive selection
Neg selec
Pos selection is what??
Favors TC that can recognize peptides presented by a self MHC
Neg selection does what?
It eliminates potentially auotreactive cells that could be activated by the peptides normally presented by mHc molecules on the surface is healthy cells
Pos selec outcomes
No binding/weak binding to MHC peptide then : alpha chain rearrangement
If still no binding the undergoes apop
Pos selc outcome
If TCR binds strongly then =pos selection
Turn off RAG
What chain is allelic exclusion used on?
Only B chain
A not subject too
If the TCR can bind to MHC why does this mean?
Can now present by the body’s set of MHC
Thymocyte is restricted
What does mHC restricted mean?
That the TCR can only respond against peptides being presented by those MHC in that persons body
The thymocyte is restricted
MHC selection
Only one of the two co receptors will be selected for
If interaction bw CD4 & MHC II then what happens to CD8
CD8 is down regulated and disappears from the cell surface only expressing CD4 now a single pos thymocyte
What does MHC II respond to and have displayed?
Displays CD4
T helper can only respond
MHC I cells express/respond to
CD8 - single pos
T cytotoxic cells can only respond
Pos selection means what will be selected?
That there will be a TCR that binds to a MHC
And that then while interaction occurs only one of the co receptors will be expressed
Positive selection is regulated by what type of cells?
Cortical epithelial cells
What do cortical epithelial cells express?
Both types is MHC
Self-peptides
TCR double positive thymocytes
What type of cells does negative selection use to regulate a:b TC?
DC and macrophages not pt of the original thymus structure
They are the BM dervived
Neg selec does what when there is engagement of the mHc of one of these specialized thymic antigen present cells by the receptor?
The rec of the auotreactive TC induces the TC to undergo apoptosis
Neg selection main pts
Through BM DC and macrophages
Present self peptides
Occurs when TCR has high affinity with the MHC leading to apop
Deletes poten self reactive thymocytes generating a repetitive of peripheral TC that is largely self tolerant
Repertoire of peripheral TC that have survived both pos and neg selection is both
Self MHC restricted
Self - tolerant
Neg selec is specific to what proteins and cell types
Insulin and B cells
What are AIRE?
TF
Expression of tissue specific genes of epith in thymus medulla
Bound to MHC I
Participate in Neg selection
Def of AIRe
APECeD
Type I diabetes
Addison’s disease
Gonadal dysfunction
How does the immune as deal with self specific TC?
- primining of mature TC- peripheral tolerance
2. TCR suppresses immune response
What is AIRE?
Basically a systemic auto imm disease
CD4 T cells are also called
T reg
CD 4 T-reg cell facts
Present in all people CD4+ Expression of CD25 on the cell surface 5-10% peripheral CD4 Thought to ordinate from the thymus Use transcription factor FoxP3 Express a:b TCR
What does only T reg cells have?
FoxP3 transcription factor
What is CD4 T reg cells activated by?
Specific MHC class II peptide
Do CD4 T reg
Cells proliferate?
No they don’t they suppress proliferation of naive TC responding to self antigen
Cd4 T reg require what?
On same ApC
Requires contact between two TC
Needs cytokines IL-10 and TGF-beta
Actions of CD T reg?
Suppress APC
By respon by helper T or t-cytotoxic
Some response agains tumors suppress or other imm response
Def of Foxp3 means what?
IPEX
Autoimmune directed towards variety of tissue
Treatment of IPEX?
BM trans from health HLA- identical sibling
T cells undergo further diff in what lymph ?
Secondary lymphoid tissue
Effector T cells are what?
Cd8
Cd4
-reg TC
-helper T
*TH1
*TH2Which is more in the periphery? Cd4 or 8?
Twice as many CD4
TCR summary
Controlled by several genes/ gene products
Somatic recomb -RAG
Junctional diversity
Beta chain -VDJ first
Try several times(4x)
B+ surrogate alpha chain CD3 flanking molecule signaling Apop or success Cell replication if successful Then Alpha chain VJ Try several times
Then we get a:b receptor
Apop or success
Then cell rep if successful
Class I deficiency
Cd4+
Cd8 -no
Class II def
No cd4
Yes CD8
Are TC long or short lived?
After thymic atrophy or theymextong TC in the periphery self Renew by cell division and are long lived
