Immunology 09 - T-Cell Development

Front 1

What are the different type of T-cells if looking at the TCR?

Back 1

alpha-beta and gamma-delta

Front 2

Which type of T-cell is most prevalent if compared by their TCRs?

Back 2

alpha-beta T-cells are the most prevalent and can be subdivided based on accessory molecules expressed on their surfaces

Front 3

What are the two subtypes of alpha-beta T-cells?

Back 3

CD4+ (augement immune responses) and CD8+ (role in killing virally infected cells)

Front 4

What is the limitation of the innate system that necessitates T-cell?

Back 4

Limited ability to recognize foreign pathogens due to the limited ability to recognize receptors on the surface of microorganisms.

Front 5

Where does T-cell development occur?

Back 5

In the thymus and begins with a commmon progenitor that originates in the bone marrow and migrates into the thymus.

Front 6

What is the role of the thymus?

Back 6

Teaching or educating the T-cells to not overly recognize self antigen, while still being able to recognize foreign antigens.

Front 7

How does a T-cell recognize antigen?

Back 7

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.

Front 8

MHC Class I

Back 8

expressed on all cells, recognized by CD8 T-cells, expresses viral antigens,

Front 9

MHC Class II

Back 9

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

Front 10

What structures composed the TCR?

Back 10

The majority have 2 polypeptide chains (alpha and beta) that are joined together. Associated with CD3 complex, and CD4/CD8 accessory molecules as well.

Front 11

What are the functions of CD4 and CD8 accessory molecules?

Back 11

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.

Front 12

From what embryological structure does the thymus originate?

Back 12

3rd pharyngeal pouch and branchial cleft.

Front 13

When does the thymus become colonized?

Back 13

At the 8th week of gestation by a lymphoid precursor cell

Front 14

How many new thymocytes does an individual produce each day from birth to adolescence? How many of those thymocytes live?

Back 14

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

Front 15

What is DeGeorge syndrome?

Back 15

Developmental abnormality that leads to absence of Thymus. This causes a lack of T cells in the blood rendering patients susceptible to opportunistic diseases.

Front 16

What is the histological structure of the thymus and what are the important cells.

Back 16

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

Front 17

What structures do thymic epithelial cells have that are important in educating T-cells?

Back 17

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.

Front 18

What do thymic epithelial cells produce to help in education of T-cells?

Back 18

Cytokines that help guide developing T-cells from the cortex to the medulla as they mature.

Front 19

What are the three major populations of thymocytes in the thymus?

Back 19

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+

Front 20

Where are the double negative T-cells found?

Back 20

The most immature cells begin in the subcapsular region of the cortex. (double negative cells)

Front 21

Where would the single positive T-cells be found?

Back 21

Mainly in the medulla.

Front 22

What percentage of DN (double negative) T-cells also lack a functional TCR?

Back 22

2/3.

Front 23

What percentage of the total T-cell population are DN T-cells?

Back 23

3-5%

Front 24

What is the most critical event during the initial steps of T-cell development?

Back 24

Beta-selection

Front 25

What is Beta-selection?

Back 25

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.

Front 26

What is important about Beta-selection in T-cell development?

Back 26

It is the first checkpoint (Checkpoint #1) in T-cell production.

Front 27

What percentage of DP cells in the thymocyte population?

Back 27

85-90%.

Front 28

What developmental steps occur to double positive T-cells? What perecentage go on to become SP T-cells?

Back 28

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)

Front 29

What are the structural characteristics of SP cells?

Back 29

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

Front 30

Are there more CD4 or CD8 T-cells

Back 30

In a ration of about 2:1, There are more CD4 T-cells than CD8 T-cells.

Front 31

What method do we use to track T-cell development?

Back 31

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

Front 32

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?

Back 32

CD44 and CD25 are the axis. CD44+ CD25- are the least mature, then DP, then CD44- CD25+, the most mature DN

Front 33

What proteins are expressed on the surface of T-cells that undergo B-gene rearrangement?

Back 33

CD44-/CD25+. DN3 cells. This is checkpoint 1, RAG are imporant for joining the different segments together.

Front 34

Where does checkpoint two occur?

Back 34

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

Front 35

The process of B-chain gene rearrangement is very similar to what process?

Back 35

Ig gene rearrangement

Front 36

What is the goal of B-chain gene rearrangement?

Back 36

produce a functional B-chain that is capable of pairing with pre-alpha chain.

Front 37

When is the pre-alpha chain expressed?

Back 37

It is constituitively expressed. It rearranges during the DP phase.

Front 38

What occurs once the rearranged B-chain and the pre-alpha chain come together?

Back 38

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.

Front 39

How does the membrane bound pre-TCR affect the survival of the T-cell?

Back 39

It sends signals that the T-cell should survive.

Front 40

Omenn's Syndrome

Back 40

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

Front 41

What does the TCR need to transmt signals internally?

Back 41

CD3 complex

Front 42

List the steps involved in preTCR signaling>

Back 42

Lck phosphorylates CD3 ITAM, ZAP 70 recruited, Lck phosphorylates ZAP70. ZAP 70 then recruits other signaling molecules

Front 43

What portion of the CD3 complex are responsible for transmitting signals?

Back 43

ITAMs, in the cytoplasmic domain. Site of phosphorylation

Front 44

What molecule activates the ITAMs of the CD3 complex?

Back 44

Lck, tethered membrane that phosphorylates the tyrosine residues of the ITAMs

Front 45

Once the ITAMs are phosphorylated what happens?

Back 45

ZAP 70 is recruited and phosphorylated and it phosphorylates other ITAMs

Front 46

SCID

Back 46

ZAP 70 altered. blocks ability to generate T cells, prone to opportunistic diseases

Front 47

What is one of the most important molecules that ZAP 70 phosphorylates?

Back 47

LAT adaptor molecule. Serves as a docking site for other signaling molecules.

Front 48

What does positive and negative selection do?

Back 48

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.

Front 49

How is specificity of the TCR assessed?

Back 49

Has to recognize peptide in context of MHC molecules. If TCR doesn't fit, no signaling cell death occurs.

Front 50

If the TCR and MHC interact during development what determines the fate of the cell?

Back 50

Either distinct positive and negative signals or intesitiy and duration determines fate.

Front 51

What are the fates during the DP stage?

Back 51

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