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Development of T Cells - Chapter 7 - Immunology
Terms in this set (49)
From where do T cells originate? And Where do they then develop?
T cells come from the bone marrow then migrate via the blood to the Thymus where they mature
Where does T cell gene rearrangement occur?
in the THYMUS (a primary lymphoid organ)
REMEMBER : there are 2 T cell lineages
these both are derived from the same T cell precursor cell
Thymus contains THYMOCYTES (immature T cells) enbedded in THYMIC STROMA
Disucss Thymus organization and where T cells are located at diff. stages of development
Thymus is composed of 1. Cortex 2. Medulla
Cortex = IMMAATURE thymocytes
Medulla = MATURE thymocytes
genetic failure to develop a thymus
Thymus is fuly developed at birth and slowly degenerates throughout life
How do T cells become committed to T cell lineage?
Upon entering the THYMUS, the progenator cells are NOT committed to the T cell lineage
1. Interact with stromal cells, signal cell to divide
2. Start to express surface proteins characteristic of T cells (CD2, CD5)
3. Cells are double negative (have neither CD8 or CD4 proteins)
Involved in the regulation of T cell development
secreted by thymic stromal cells
helps commit cell to T cell lineage
binds to receptor on CD34+ cells (stem cell)
Notch - 1
Analagous to Pax-5 ( associated with B cells )
Notch -1 is a cell surface receptor on thymocytes
binds to thymic epithelial cells
goes to thymocyte nucleus to activate gene essential for T cell developement
What happens in the absence of Notch - 1 receptor on lymphoid progenitor cell?
Progenitor will commit to B cell lineage in place of that of T cell lineage
On T cells, what is expressed first, CD4 or CD8?
Alpha chain is NOT subject to allelic exclusion, thus we can truly get more than one type of Alpha chain on the surface of an individual T cell
this occurs in thymocytes
means the cell is only able to respond against peptides being presented by those MHCs in that person's body
AIRE (autoimmune regulator)
activates the expression of specific genes in subpopulation of epithelial cells in thymus medulla to make peptides that are tissue specific (like insulin)
these peptides will ONLY bind to MHC Class 1
Participate in Negative Selection
T Regulatory Cells
suppress immune response
combat the T cells that are still self reactive (those that have sneaked through negative selection)
these cells are CD4+
transcription factor expressed in CD4+ T-regulatory cells
expressed on T regulatory cells
In the periphery, are there more CD4+ or CD8+ cells?
2x more CD4+ cells in periphery
Where do T cells derive from? Where do they mature? Where does gene rearrangement occur for developing t cells?
Derived from Bone Marrow Stem Cells
T cells mature in the THYMUS (a primary lymphoid organ)
Gene rearrangement occurs in the Thymus, NOT the bone marrow
REMEMBER : the 2 subsets of t cells ( alpha/beta, gamma/delta) come from the same precursor cell and develop parallely
In thymus, where are immature thymocytes compared to mature thymocytes?
maturity increases from outside to inside
Cortex - IMMATURE thymocytes
Medulla - Mature Thymocytes
What must you memmber about the process of committing bone marrow stem cells (CD34) to the T cell lineage?
NOTE : Stem cells are NOT committed to T lineage simply by migrating to the thymus
Committment occurs following interaction with Thymic STROMAL cells
The are signaled to divide, double negative (Neither CD4 or CD8+)
What is secreted by thymic stromal cells that contributes to the committment of stem cells (CD34) to the T cell lineage?
How to rememeber this : TCR genes are located on genes 7 and 14, again, this is a multiple of 7
CD34+ stem cells have IL-7 receptors
what are the two major things that help commit stem cells to T cell lineage?
1.) IL-7 from thymic stromal cells binding to recepto on CD34+ stem cells
2.) Notch - 1
-notch - 1 is a receptor on the surface of Tthymocytes
- this receptor binds to the thymic epithelial cells
- drives T cell differentiation
IMPORTANT : this is analagous to Pax-5
NOTE : w/o Notch-1 the lymphoid progenitor will commit to the B cell lineage of development
In TCR rearragnment, what rearranges first?
Beta, Gamma, and Delta are all rearranging parallely
REMEMEBER : if Beta rearrangment is achieved Before that of gamma/delta, the cell is still NOT committed to Alpha/beta subset
When do thymocytes become double positive cells (having both CD4 and CD8)?
Once the Beta chain of the TCR is successfully rearranged, CD4 AND CD8 appear on cell surface.
NOTE : however, this DOES NOT mean that the cell is committed to alpha/beta cell type
REMEMBER : after the beta chain has successfully rearranged, cell become double positive, then the alpha chain rearrangment is commenced. BUT, the gamm and delta chains continue to differentiate
What must TCR assemble with in the ER in order to exit to the membrane?
What is done with the beta chain after it has successfully rearranged itself?
newly synthesized beta chain migrates to ER
pT-alpha (invariant alpha chain) is used to test the structural integrity and binding abilities of the Beta chain of TCR
What occurs if the Beta chain is able to associate with the pT-alpha invatiant alpha chain?
complex assembles with CD3
Pre-T-Cell receptor is now formed
Once the PRE t cell receptor is formed, what does the signaling do?
the Pre t cell receptor tells the cell to STOP the rearrangment of Beta, gamma, and delta chains
Pre t cell receptor is what is used to tell the cell to make thymocyte double positive (put on CD4 AND CD8)
HOWEVER, alpha chain rearrangment must push on
Discuss the rearrangment of Beta chain portion of the T-cell receptor?
IMPORTANT : Thymocytes can make FOUR (4) attempts to rearrange a beta chain gene
WHY? : because the beta chain has 2 constant regions on each homologous chromosome, therefore containing a TOTAL of four (4) beta constant regions in the gene
NOTE : there are TWO (2) constant regions for the Beta gene
COMPARRISON : this is NOT possible for hte Ig Heavy chain genes
What are the steps to T cell development after the Beta chain rearrangment has been successful?
1. RAG is SUPPRESSED
2. Pre T cell receptor "armed" cells proliferate, creating a bunch of cells (clones) with identical Beta chain and thus identical Pre T-cell receptors
3. Formation of the Pre T-cell signals cells to make the thymocyte DOUBLE POSITIVE
REMEMBER : the CD4 is expressed first, followed by CD8
4. Large DOUBLE POSITIVE Thymocytes
5. Small DOUBLE POSITIVE Thymocytes
6. RAG is REACTIVATED!
7. Gamma, delta, and alpha locus rearrangments commence / continue
NOTE : at this point, BETA chain rearrangment has been signaled to STOP
Why is the Beta chain signaled to stop rearranging after the successful initial rearrangment?
This is due to ALLELIC EXCLUSION on the BETA chain gene
This ensures that each cell type has ONLY ONE(1) successful beta chain rearrangment
NOTE ON ELLECIC EXCLUSION : important to remember that ALPHA chain is NOT subject to ALLELIC EXCLUSION
REMEMEBER : the successful rearrangment of alpha chain ELIMINATES the linked delta (symbol that does NOT look like a y, the y is the gamma, duh!) locus. WHY?, you ask Steve?
This is simple. It is because the delta locus is situated between the V-alpha and J-alpha gene segments on Chromosome 7
THUS, remembering what the picture looks like from the book, the Delta-chain locus will exit as a plasmid-type piece of DNA. (Circular, continuous DNA structure).
What happens once the ALPHA chain is successfully rearranged?
Successfully arranged ALPHA chain translocates to the ER
Tested for it ability to bind to the BETA chain
Succesful interaction with BETA chain?
..... then rearrangment stops and TCR is formed
Unsuccessful interaction of Alpha / Beta chain?
.... then that ol' alpha chain gets right back to it, rearranging itself, hoping for another successful gene rearrangment. If it is successful then great, the TCR is formed. It not it keeps trying till all possibilities are exhausted. Cell will die via apoptosis.
Positive Selective vs. Negative Selection
Which occurs first?
Postive Selection - Ensure that the recently synthesized TCR is able to recognize peptides presented by SELF-MHC molecules
vs. .............. ............. ..............
Negative Selection - elimination of potentially autoreactive cells that could be activated by the peptides normally presented by MHC molecules on the surface of health cells. this is ensuring self tolerance!
Postive Selection occurs first
Regulated by CORTICAL EPITHELIAL CELLS
these cells express BOTH MHC CLass - 1 and MHC CLass - 2
What happens if the TCR does not bind the MHC molecule?
alpha chain will rearrange again
if still no binding after Alpha chain re-rearrangment, cell dealth pursues
MHC Restricted : DEFINE
Thymocytes are considered this
Means that thymocytes can only respond a gainst peptides being presented by those MHC in that person's bodu
What cells are responsible for NEGATIVE SELECTION?
Bone marrow derived dendritic cells and macrophages
these cells present peptide fragments that are "self"
if the thymocyte binds TOO strongly to the self peptide being presented in the MHC molecules, the cell is killed by apoptosis
BIG PICTURE : the function of negative selection of Thymocytes is to eliminate those future T cells that are self-reactive (would attach the body's own tissues and structures) and thus generates a team of T cells in the periphery that is largely SELF-TOLERANT
AIRE ( autoimmune regulator )
This transcription factor iniatiates the expression of tissue specific genes in subpopulations of epithelial cells of the thymus medulla
this aides in NEGATIVE SELECTION
there are some products that are only made in special areas of hte body (i.e. insulin in Beta cells of pancreas) and the Maturing thymocytes would not have been exposed too. this ensures that death of cells that are reactive to tissue specific self products
T-Regulatory Cells (CD4 or CD8?)
What surface molecule distinguishes this subset of T cells?
FUNCTION : Suppression of immune response
NOTE : Suppression of autoreactive T cells by regulatory T cells requires them to interact with the same antigen presenteing cell
These cells are CD4+ !!!!!!!!!!
Distinguished : by CD25
so these cells are CD4+ , CD25+
Utilize the ALPHA / BETA T- cell receptor type
expresse selectively by CD4+ CD25+ T-Regulatory Cells
How do T regulatory cells function?
They bind to MHC - Class 2 molecules on Antigen presenting cell
DO NOT proliferate, instead they suppress the activity of the Naive T cell that is ALSO BOUND to the SAME(!!!) Antigen presenting cell
REQUIREMENT : actual, physical cell - to - cell contact between the regulatory t cell and the autoreactive T cell
FUNCTION : regulatory T-cells are used to stop autoimmunity against T cells that were NOT killed via Negative Selection in the Thymus
THUS... negative selection can fail in its attempt to make self tolerance in the T cell populations the thymus is generating
REMEMBER : Mature T cells live MUCH LONGER than mature B cells in the periphery (may circulate for YEARS)
What are the properties of the IgM antibody?
What happens in Autoimmune Hemolytic anemia?
what is the function of the IL-2 cytokine?
What is the function of granzymes?
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