Glossary of Immunology 09 - T-cell development

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What are the different type of T-cells if looking at the TCR?
alpha-beta and gamma-delta
Which type of T-cell is most prevalent if compared by their TCRs?
alpha-beta T-cells are the most prevalent and can be subdivided based on accessory molecules expressed on their surfaces
What are the two subtypes of alpha-beta T-cells?
CD4+ (augement immune responses) and CD8+ (role in killing virally infected cells)
What is the limitation of the innate system that necessitates T-cell?
Limited ability to recognize foreign pathogens due to the limited ability to recognize receptors on the surface of microorganisms.
Where does T-cell development occur?
In the thymus and begins with a commmon progenitor that originates in the bone marrow and migrates into the thymus.
What is the role of the thymus?
Teaching or educating the T-cells to not overly recognize self antigen, while still being able to recognize foreign antigens.
How does a T-cell recognize antigen?
Need to interact with specialized cells (APCs) that present processed antigen on the surface of cells. Such that CD4 and CD8 T-cells can recognize the antigen.
MHC Class I
expressed on all cells, recognized by CD8 T-cells, expresses viral antigens,
MHC Class II
expressed on B-cells, dendritic cells, macrophages. Only recognized by CD4+ T-cells. Aid the immune response by telling the macrophage to degrade its ingested antigen or telling B cells to produce antibodies
What structures composed the TCR?
The majority have 2 polypeptide chains (alpha and beta) that are joined together. Associated with CD3 complex, and CD4/CD8 accessory molecules as well.
What are the functions of CD4 and CD8 accessory molecules?
Help strengthen the engagement of the interaction between the TCR and MHC. These molecules allow the cell to signal at a lower threshold, but you must have accessory molecules to signal properly.
From what embryological structure does the thymus originate?
3rd pharyngeal pouch and branchial cleft.
When does the thymus become colonized?
At the 8th week of gestation by a lymphoid precursor cell
How many new thymocytes does an individual produce each day from birth to adolescence? How many of those thymocytes live?
50 million produced each day with only 1-2 million surviving to become mature T-cells. Very inefficient because you get rid of T-cell recognizing self antigen
What is DeGeorge syndrome?
Developmental abnormality that leads to absence of Thymus. This causes a lack of T cells in the blood rendering patients susceptible to opportunistic diseases.
What is the histological structure of the thymus and what are the important cells.
Outer cortex and Inner medulla. There are cortical and medullary epithelial cells that play are role in negative and positive selection, respectively. Dendritic cells and macrophages also participate in negative selection and are found in mainly in the medulla
What structures do thymic epithelial cells have that are important in educating T-cells?
Thymic epithelial cells have a high density of MHC I and MHC II molecules which are important for educating T-cells and eliminating those that recognize self antigen.
What do thymic epithelial cells produce to help in education of T-cells?
Cytokines that help guide developing T-cells from the cortex to the medulla as they mature.
What are the three major populations of thymocytes in the thymus?
1. immature double negative cells lacking both TCR and CD4/CD8
2. double positive T-cells. TCR + and CD4+/CD8+
3. single positive TCR+ CD4+ or CD8+
Where are the double negative T-cells found?
The most immature cells begin in the subcapsular region of the cortex. (double negative cells)
Where would the single positive T-cells be found?
Mainly in the medulla.
What percentage of DN (double negative) T-cells also lack a functional TCR?
What percentage of the total T-cell population are DN T-cells?
What is the most critical event during the initial steps of T-cell development?
What is Beta-selection?
which is the rearrangement of the B-chain gene to generate a mature and funcitonal B-chain product which can pair with an pre-alpha chain. This goes on to make a functional TCR on the surface of these cells which enable them to receive signals tell the cell to survive and differentiate.
What is important about Beta-selection in T-cell development?
It is the first checkpoint (Checkpoint #1) in T-cell production.
What percentage of DP cells in the thymocyte population?
What developmental steps occur to double positive T-cells? What perecentage go on to become SP T-cells?
DP T-cells have both CD4 adn CD8 expressed on their surfaces. During development 95% of these cells will die because the fail to recognize self MHC. The cells that react to self antigens are also deleted. (Checkpoint 2)
What are the structural characteristics of SP cells?
CD4+CD8- or CD4-CD8+ T-cells that have high levels of CD3 and a functional TCR. Functionally mature and destined to leave the thymus
Are there more CD4 or CD8 T-cells
In a ration of about 2:1, There are more CD4 T-cells than CD8 T-cells.
What method do we use to track T-cell development?
Flow cytometry which detects surface antigens using fluorescently-tagged antibodies that target either CD4 or CD8. Can also use CD44 and CD25 to classify double negative T-cells
When using flow cytometry of double negative T-cells what are the axis of the graph and which are the most mature and immature cells?
CD44 and CD25 are the axis. CD44+ CD25- are the least mature, then DP, then CD44- CD25+, the most mature DN
What proteins are expressed on the surface of T-cells that undergo B-gene rearrangement?
CD44-/CD25+. DN3 cells. This is checkpoint 1, RAG are imporant for joining the different segments together.
Where does checkpoint two occur?
after a functional pre-tcr is put on the surface, between the DP and SP stages. This is where the cells undergo both positive and negative selection
The process of B-chain gene rearrangement is very similar to what process?
Ig gene rearrangement
What is the goal of B-chain gene rearrangement?
produce a functional B-chain that is capable of pairing with pre-alpha chain.
When is the pre-alpha chain expressed?
It is constituitively expressed. It rearranges during the DP phase.
What occurs once the rearranged B-chain and the pre-alpha chain come together?
Brought to the surface of the cell. Spontaneous signalling occurs. Lck, RAGs, ZAP 70, LAT pathways are turned on. gene transcription turned on as well.
How does the membrane bound pre-TCR affect the survival of the T-cell?
It sends signals that the T-cell should survive.
Omenn's Syndrome
In the SCID (Severe Combined Immunodeficiency Diseases) family. Due to a lack of RAGs, so you can't recombine Beta chain no pre-TCR formed, B-cell rearrangement also affected, prone to opportunistic diseases
What does the TCR need to transmt signals internally?
CD3 complex
List the steps involved in preTCR signaling>
Lck phosphorylates CD3 ITAM, ZAP 70 recruited, Lck phosphorylates ZAP70. ZAP 70 then recruits other signaling molecules
What portion of the CD3 complex are responsible for transmitting signals?
ITAMs, in the cytoplasmic domain. Site of phosphorylation
What molecule activates the ITAMs of the CD3 complex?
Lck, tethered membrane that phosphorylates the tyrosine residues of the ITAMs
Once the ITAMs are phosphorylated what happens?
ZAP 70 is recruited and phosphorylated and it phosphorylates other ITAMs
ZAP 70 altered. blocks ability to generate T cells, prone to opportunistic diseases
What is one of the most important molecules that ZAP 70 phosphorylates?
LAT adaptor molecule. Serves as a docking site for other signaling molecules.
What does positive and negative selection do?
ascertain whether the alpha chain has been functionally rearranged so it may pair with the Beta chain to form a mature TCR. Generate a TCR that recognizes self MHC.
How is specificity of the TCR assessed?
Has to recognize peptide in context of MHC molecules. If TCR doesn't fit, no signaling cell death occurs.
If the TCR and MHC interact during development what determines the fate of the cell?
Either distinct positive and negative signals or intesitiy and duration determines fate.
What are the fates during the DP stage?
1. T-cell death by neglect, can't recognize MHC
2. TCR has good MHC recognition, but low affinity inteaction with self antigen, survives via positive selection
3. TCH has good MHC recognition and tight fit with antigen, death by neg. selection

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