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40 Cards in this Set

  • Front
  • Back
Where do T cells come from?
T cells develop from progenitors that are derived from pluripotent stem cells located in the bone marrow
Where does T cell development take place?
The thymus
Where is the thymus located? What are the regions of the thymus?
The thymus is located in the anterior mediastinum. Histologically the thymus has two regions:
-Peripheral cortex: densely populated with lymphoid cells
-Central medulla: Less lymphocyte rich, contains dendritic cells and macrophages
What determines if a cell will become a T cell?
Signals from the thymic stroma
Describe the cortex of the thymus
It is located in the periphery of the thymus. It is rich in lymphocutes and contains stromal cells. It has epithelial cells which determine the fates of the lymphocytes and how they mature and develop into competent immune cells.
Describe the medulla of the thymus
The medulla is very rich in macrophages and dendritic cells. You can see in the histology that the cortex is a very dense region and how cells are more scattered through in the medulla.
Where do T cell progenitors enter the thymus?
The cortico-medular region
What is the key signal for the commitement of the hematopoetic progenitors to become T cells?
What is the importance of signals from the stroma?
Signals from the stroma promote T-cell commitment, differentiation, and proliferation
What is needed for fully functional T cell development?
Both lymphoid progenitors and the thymic stroma
What are the early stages of T-cell development?
-Initially early thymocytes (DN) are not committed to the T-cell lineage
-Double Negative 1-> Kit+CD44+CD25-
Double Negative 2-> Kit+CD44+CD25+
Double Negative 3-> Kit+CD44-CD25+
Double Negative 4-> Kit-CD44-CD25-
-Double negative T cell development is driven by signals from stroma such as NOTCH1, IL-7, and cKit
Why are they called double negative cells?
Because they dont express CD4 and CD8
What happens after the DN4 stage?
T cells become double positive T cells
What controls the development of T cells?
Signals from the thymic microenvironment
What makes T cells functionally competent?
Gene rearrangement
What is synchronized with gene rearrangement?
Changes in surface antigens
What event is synchronized with the DN2 stage? DN3 stage? DN4 stage?
DN2: Start of TCRbeta (D-J) rearrangement
DN3: Continues TCRbeta rearrangement (V-DJ)
DN4: TCRbeta-preTCR signaling blocks further TCRbeta rearrangement
What event is synchronized with the DP stage? SP stage?
DP-> TCR alpha rearrangement and positive selection
SP-> Negative selection and exit from the thymus
How long does it take T cells to develop from DN to SP?
3 weeks
Describe the movement of T cells during their development
During this process the cells migrate through the thymus and interact with different compartments in the thymic stroma. This process is orchestrated and coordinated with the rearrangement of the T cell receptors, changes in the surface of antigens, and changes in the way these cells behave.
Describe alpha-beta T cells
They are the most abundant type of T cell. They are responsible for the adaptive immune response. They have an alpha beta TCR on the surface
Describe gamma-delta T cells
They are a minor population. They recognize lipid antigens in the gut (between innate and adaptive immune responses). They have a gamma-delta TCR on the surface. They play a role in the intermediate between the innate and adaptive immune responses.
Describe the lineage choice between gamma-delta and alpha-beta T cells
-Gamma, delta, and beta are all rearranged at the same time.

-A successful gamma-delta rearrangement drives a strong signal and promotes gamma-delta T-cell development

-A successful TCRbeta rearrangement drives a weaker preTCR signaling that drives alpha-beta lineage

-TCRalpha rearrangement deletes TCRdelta, blocking development into the gamma-delta lineage.

-The strength of the NOTCH signal also influences alpha-beta vs. gamma-delta choice
Describe the creation of the TCR
During the process of rearrangements, if the cell completes a successful gamma delta rearrangement, this will produce a protein on the surface that will signal the cell to become a gamma delta T cell. If there is a successful TCRbeta rearrangement before the gamma-delta commitment is committed then the cell would signal differently. The signal is mediated by the preTCR complex, which is composed of the TCRbeta chain and a non-rearranged TCRalpha chain. It makes a weak signal, but it does not seal the fate of the cell. If the cell has a TCRbeta at the surface they signal through preTalpha , the proliferate and now have a chance to rearrange the alpha chain and become alpha beta cells.
What event in the development of the TCR seals its fate to the alpha-beta pathway? Why?
Alpha chain rearrangement. When the alpha chain begins to rearrange it deletes the delta chain.
Describe TCRbeta rearrangement
-The DJ are joined in DN2, then V joins to the already rearranged DJ in DN3

-If successful a TCRbeta is express with the preTCRalpha in DN4

-The structure of TCRbeta with two D J clusters and C chains allows two full rounds of recombination

-If unsuccessful and no effective gamma-delta recombination then the cell dies
What is the importance of preTCRalpha signaling?
PreTCRalpha signaling plays a key role in making sure we have a broad enough immune repertoire. This is because the process of generating the T cell receptor is very inefficient. Most cells during development in the thymus are going to die by apoptosis. You need a step of proliferation in the middle of the differentiation to ensure that once you have a successful beta rearrangement you expand the population so that some of these cells would get a chance to successfully rearrange their alpha chains. In the end around 2% of the cells that enter are successfully developed into functional T cells. The beta-preTCRalpha signal is through a LCK tyrosine kinase and this triggers the gradation of rag2. Cells can only successfully rearrange one beta chain.
Explain preTCR signaling
-Beta chain plus invariable preTCRalpha chain in association with signaling complex proteins

-Signals through the LCK tyrosine kinase

-Triggers degradation of rag2 blocking further rearrangement of the beta chain

-Induces proliferation during DN4

-Drives expression of the CD4 and CD8

-PreTCR generates a pool of cells with a single beta chain that will rearrange alpha

-Mature T cells can have the same beta chain and different alpha chains

-After preTCRalpha signaling cells have to stop prolierating to rearrange alpha
Describe TCRalpha rearrangement
-Occurs in DP cells
-It does not have D segments, only V-J
-Recombination occurs only if beta is successfully expressed
-60 J segemenet and lots of V segments allow multiple rounds of recombination
-A successful TCRalpha rearrangement does not block recombination.
-TCRalpha recombination is blocked by recognition of self-MHC complexes during positive selection.
-DP cells live for only 3-4 days unless rescued by TCR stimulation and positive selection
Where is the delta chian locus located?
Inside the alpha chain
What is T cells selection?
The process of rescue from cell death and maturation to SP CD4 or SP CD8 cells upon recognition of MHC-self peptides

Negative selection TCR receptors that respond too strongly to self peptide are eliminated as potentially self reactive
What are the three key elements during T cell selection?
The T cells 1) must be functional in their ineraction with dendritic cells and recognize MHC complexes
2) They are safe so they will not actually recognize self antigen
3) They are diverse enough so that they would recognize foreign antigen in a competent way.
Where does positive selection occur? Where does negative selection occur?
Positive selection: In the cortex
Negative selection: In the medulla
What mediates positive selection? Negative selection?
Positive selection: Interaction with epithelial cells
Negative selection: Interaction with dendritic cells and macrophages
What makes up the TCR?
-Alpha chain
-Beta chain
-CD3 (delta, epsilon)
-Zeta chain
Explain CD4 CD8 lineage fate
-Positive selection is coupled with CD4 and CD8 cell fate specification

-If the CD4CD8 cell TCR recognizes MHC I the T cell must have CD8 to be functional during MHC I immune reaction
-If the CD4CD8 cell TCR recognizes MHCII the T-cell must have CD4 to be functional during MHCII immune reaction

-CD4 cells will have an expression program tha llows cytokine secretion while CD8 cells will have an expression program that makes them capable of cell killing.
Explain positive selection
-Positive selection occurs selectively in the cortex
-A CD4CD8 T cellexpresses TCR and encounters an epithelial cell expressing MHC class I:self peptide
i) successful interaction drives positive selection and generates a CD8 SP (cytotoxic)
ii) Unsuccessful interaction drives continuous rearrangement of alpha to generate a different TCR and try again
-A CD4CD8 cell expressing TCR and encounters an epithelial cell expressing MHC class II:self peptide
i) Successful interaction drives positive selection and generates a CD4 SP (cytokine secreting)
ii) Unsuccessful interaction drives continuous rearrangement of alpha to generate a different TCR and try again

If after multiple encounters there is no self recognition and the alpha chain runs out of recombination options the cell dies by apoptosis: >95% of the cells to be positively selected and undergo programmed cell death.
Explain negative selection
-Interaction of TCR with an MHC-peptide in the thymus triggers cell death
-The thymic stroma is fully competent to eliminate autoreactive clones
-AIRE (autoimmune regulator) drives expression of extrathymic antigens such as insulin in the thymic stoma
-Negative selection is mainly driven by bone marrow derived dendritic cells and macrophages in the medulla
Describe early thymocytes
They lack expression of CD4 and CD8 and are not committed to the T-cell lineage (they can generate B-cells and NK cells)
Describe small DP cells
They upregulate the expression of CD3, rearrange TCRalpha and undergo positive and negative selection