"Microbiology/Immunology T Cell Development" MARY

Question 1

The _____ is the major site of T-cell development.

Answer 1

Thymus

Question 2

When we say that T-cells become lineage committed in the thymus, what does this mean?

Answer 2

CD4 and CD8

Question 3

T/F: Each of us has a unique, self-restricted TCR repertoire.

Answer 3

True.

Question 4

T-cells are tolerized to what in the thymus during T-cell development?

Answer 4

Self antigen

Question 5

Explain the concept of MHC restriction.

Answer 5

A few things:

1. HLA is another way of saying MHC
2. MHC I is recognized by all nucleated cells.
3. MHC II are only on APCs.
4. The TCR must recognize both the antigen (peptide) AND the MHC complex

Question 6

T/F: CD4 and CD8 lineage T-cells recognize different MHC molecules.

Answer 6

True. CD8 binds to the alpha-3 domain of MHC I. CD4 binds to the beta-2 domain of MHC II.

Question 7

T/F: TCR development involves gene rearrangements.

Answer 7

True

Question 8

DiGeorge syndrome involves what deficiency?

Answer 8

Human T-cell immunodeficiency

Question 9

What is a “nude” mouse”

Answer 9

Lacks hair AND thymic epithelial cell differentiation bc of loss of transcription factor. Can use to study T-cell immunodeficiency.

Question 10

What forms the thymus in embryonic/fetal development?

Answer 10

3rd pair of pharyngeal puch (endoderm) and cleft (ectoderm). 1st hematopoietic precursors are planted in the thymus at 8 weeks gestation. Thymus produces chemotactic factors that attract T-cell precursors.

Question 11

B-cells are born in the bone marrow and grow in the thymus. Presuming they make it out of the thymus, what are their next destinations?

Answer 11

Secondary lymphoid tissue, ie GI tract, spleen, lymph nodes.

Question 12

T-cell precursors are also known as:

Answer 12

Prothymocytes

Question 13

How do prothymocytes enter and leave the thymus?

Answer 13

Enter through the corticomedullary junction, exit through the medulla venules. **Migration is influenced by chemokines and sphingosine 1-phosphate receptors

Question 14

How does flow cytometry use “single cell” technique?

Answer 14

A graph plots each cell as a dot, and the clusters represent common populations of cells, for example the graph on page 321. Know how to read these!!

Question 15

T-cells early in development are:

(a) double negative
(b) double positive
(c) single positive

Answer 15

(a) double negative, using cell surface markers to identify stage

Question 16

CD2 receptor, found in double negative early T-cells, is for what function?

Answer 16

Cell signaling and adhesion

Question 17

Give the steps in lineage commitment, starting with the CD2 + “double negative” (-CD4/-CD8) cells.

Answer 17

1. Cell becomes gamma-delta and leaves thymus (function unknown) OR becomes alpha-beta, the typical T-cell.
2. If becoming an alpha-beta cell, cell undergoes beta, gamma delta rearrangements and becomes double positive (+CD4/+CD8) - pre-TCR assembly -
   2b. Cell tests beta chain (first checkpoint).
3. Cell can “short circuit” and still become gamma-delta cell, or can undergo alpha, gamma, delta rearrangements.
4. If successful, alpha part is done and cell is a committed alpha-beta cell.

Question 18

What is the main reason why most genetic rearrangements in T-cell development fail?

Answer 18

Reading frame issues

Question 19

How does a pre-TCR “test” its beta chain?

Answer 19

Goes to the surface with a helper molecule because it will not go alone (heterodimer –> superdimer –> pre-T-cell receptor)

Question 20

How many attempts can be made to achieve a productive rearrangement of the beta chain locus? How this different from alpha chain building?

Answer 20

Two beta chain attempts. Alpha has more chances because it can try further and further upstream regions, and has 3 or more chances to produce a functional alpha chain.

Question 21

During the alpha chain rearrangements in T-cell receptor development, what region is not used?

Answer 21

D region. Once this chain is removed, the piece must become an alpha chain.

Question 22

During what stages of TCR development can RAG-1 and RAG-2 be identified?

Answer 22

During the rearrangements of beta and alpha chains.

Question 23

When does a developing T-cell become double positive?

Answer 23

At the end of successful beta and alpha chain creation.

Question 24

In what section of the thymus do progenitor cells proliferate?

Answer 24

Medulla

*Cells go back into medulla once they are SP committed to test their MHC interactions before leaving the thymus.

Question 25

In what section of the thymus to T-cells commit to being T-cells and undergo beta and alpha chain creation?

Answer 25

Cortex

Question 26

What cells are responsible for selecting alpha-beta T-cells in the thymus, once they are DP? How do they test for this?

Answer 26

Cortical epithelial cells, by their MHC binding (moderate and strong binding proceed, weak or no binding apoptose)

Question 27

How does positive selection for a single lineage occur?

Answer 27

Whichever MHC class on the thymic epithelial cells fits better, CD4 (MHC II) or CD8 (MHC I). Then the T-cell will go on to become an exclusive lineage (single positive thymocyte).

Question 28

What cells are involved in negative selection of T-cells in the thymus? What is going on?

Answer 28

Dendritic cells, macrophages, and others. Moderate MHC binding is good - T-cell lives, tight binding is bad, T-cell dies. This is to protect against autoimmunity.

Question 29

T/F: Presentation os self-peptides from hematopoietic cells plays little role in shaping T-cell repertoire.

Answer 29

FALSE. This is a very important step to protect against T-cells reacting with self cells.

Question 30

What transcription factor is present in the thymic medulla and helps to protect against autoimmunity, for example, peripheral tissue specific antigens such as insulin?

Answer 30

The autoimmune regulator (AIRE) is a protein that in humans is encoded by the AIRE gene. AIRE is a transcription factor expressed in the medulla of the thymus and controls the mechanism that prevents the immune system from attacking the body itself.

Question 31

What is the difference between avidity and affinity?

Answer 31

Avidity refers to the accumulated strength of multiple affinities of individual non-covalent binding interactions, such as between a protein receptor and its ligand, and is commonly referred to as functional affinity.

Question 32

What is the avidity model of T-cell selection?

Answer 32

The final determination of T-cell survival, whereby T-cells that bind moderately to self-MHC peptides are selected for final maturation.

Question 33

What are regulatory T-cells?

Answer 33

A special type of CD4 cells involved in moderating other T-cells and promoting tissue tolerance to self antigen.