L10: T Cell Maturation and Differentiation

Question 1

What does T cell repertoire self-MHC restriction means?

Answer 1

Cannot recognize foreign peptide unless it is presented by self-MHC class I or class II molecules

Question 2

What does T cell repertoire self-tolerance mean?

Answer 2

T cells don’t recognize either self-MHC alone or self -MHC that has self peptide

Question 3

Where does T cell maturation occur?

Answer 3

Thymus

Question 4

What are the 2 sections of the thymus? What kinds of cells do they contain?

Answer 4

Outer cortex: cortical epithelial cells and other cells

Inner medulla: bone-marrow derived dendritic cells, medullary epithelial cells and macrophages

Question 5

Where does the pluripotent stem cell enter the enter the thymus?

Answer 5

In the cortex

Question 6

What is a pluripotent stem cell undergoing maturation called?

Answer 6

Thymocyte

Question 7

What surrounds developing thymocytes?

Answer 7

Epithelial cells of the thymus form a network surrounding developing thymocytes

Question 8

When stem cells enter the thymus, do they express any T cell lineage specific markers?

Answer 8

No

Doesn’t have TRC or CD8 or CD4

Question 9

What occurs before positive and negative selection?

Answer 9

Once they go into cortex and proliferate, there is expression of coreceptors that occurs on cell surface and rearrangement of T cell receptor alpha, beta chain genes

Question 10

Is positive or negative selection first?

Answer 10

Positive selection

Question 11

What occurs in positive selection?

Answer 11

Thymocytes that recognized self-MHC class I or class II will be selected; those that don’t recognize them (or those than bind very weakly) will die by apoptosis

Question 12

What occurs in negative selection?

Answer 12

Thymocytes that recognize self-MHC class I or II either by itself or w/ self-peptide will be eliminated

Question 13

How do T cells that express gamma, delta TCR mature?

Answer 13

We have no idea

Question 14

What process ensure that T cells are self-MHC restricted?

Answer 14

Positive selection

Question 15

What process ensures that T cells are self-tolerant?

Answer 15

Negative selection

Question 16

List the checkpoints in lymphocyte matureation

Answer 16

Apoptosed if there is failure to express pre-lymphocyte receptor

Apoptosed if failure to express antigne receptor

Apoptosed if fail to express receptors that recognize self-MHC

Apoptosed if they recognize self-MHC + self-peptide

Question 17

What kind of receptor do majority of T cells express?

Answer 17

Alpha, beta chain receptor

Question 18

What do alpha chains and beta chains consist of?

Answer 18

A variable and constant region and a transmembrane region

Question 19

What are thymocytes that do not yet express any T cell lineage specific markers called?

Answer 19

Double-negative since they don’t express CD4 and CD8

Question 20

Describe the stages of double-negative (DN) thymocyte development

Answer 20

DN1: CD44+, CD25-

CD44 is a cell adhesion molecule that could enable it to bind to the mesh of epithelial cells as they mature in the cortex

DN2: CD44+ , CD25+

After this, DN2 cells begin to rearrange the β-chain locus, becoming DN3

DN3: CD44-low, CD25+

DN3 cells are arrested until they productively rearrange the the β
-chain locus; the in-frame β
chain then pairs w/ a surrogate chain called pTα
to form the pre T-cell receptor (pre-TCR) and is expressed on the cell surface →triggers entry into the cell cycle →expression of small amounts of pTα:β in association w/ CD3 signals cessation of β-chain rearrangement and rapid proliferation, causing loss of CD25

DN4: CD44-, CD25-

Eventually, DN4 cell stop proliferating and CD4 and CD8 are expressed

Question 21

Describe the stages of double-positive thymocyte development

Answer 21

Are CD4+ and CD8+

Small CD4+, CD8+ cells begin efficient rearrangement of α-chain locus → cells then express low levels of an α:β T-cell receptor and the associated CD3 complex and are ready for selection → most cells die by failing in positive selection or in negative selection → some are selected to mature into CD4 or CD8 single-positive cells → leave thymus

Question 22

What must thymocytes express before positive and negative selection can occur?

Answer 22

A functional T cell receptor α:β chain on cell surface and the coreceptors CD4 and CD8

Question 23

Since there is a lot of death by apoptosis occuring for T cells in the thymus, what clears up the debris?

Answer 23

Macrophages ingest developing T cells that undergo apoptosis in the thymic cortex

Question 24

What are the 2 distinct lineages of thymocytes produced in the thymus?

Answer 24

α:β thymocyte receptors

γ:δ thymocyte receptor

Question 25

Where are thymocytes at different developmental stages found in the thymus?

Answer 25

DN1: corticomedullary junction DN2, DN3, DN4, immature double-positive in cortex Mature CD4+, CD8- or CD4-, CD8+ thymocytes are found in medulla

Question 26

Where do positive and negative selection take place?

Answer 26

Positive in cortex | Negative mostly in medulla

Question 27

When β chain is productively rearranged and expressed on cell surface, what stabilizes it?

Answer 27

A pre-T α chain

Question 28

What gene segements do the α and β chains have? What is the sequence of segment binding of the chain regions?

Answer 28

α: V, J, C V to J β: V, D, J, C D to J V to DJ

Question 29

Rearrangement of which chain of the T cell receptors occurs first?

Answer 29

β chain

Question 30

What is the role of pre-T cell receptors?

Answer 30

Signals→ Cell becomes permissive for TCR α-chain locus arrangement Stimulates expression of CD4 and CD8 coreceptors Stimulates proliferation Stops additional TCR β-chain locus arrangements (allelic exclusion)

Question 31

Describe the time course of appearance of α:β thymocytes and γ:δ thymocytes

Answer 31

In very early days of gestation, there is high frequencey of γ:δ thymocytes By birth and as they become an adult, there is very low γ:δ thymocyte expression Converse pattern is seen for α:β thymocytes

Question 32

What is the signaling molecule associated w/ T cell receptors?

Answer 32

CD3

Question 33

In positive selection, how do they known which thymocytes bind to self-MHC?

Answer 33

Bc self-MHC is expressed on epithelial cells of the cortex and thymocytes that can bind them will bind them

Question 34

What determines co-receptor specificity of thymocytes?

Answer 34

MHC molecule that induce positive selection determine co-receptor specificity MHC class I → only CD8+ T cells mature MHC class II → only CD4+ T cells mature

Question 35

What cells mediate positive selection?

Answer 35

Thymic cortical epithelial cells

Question 36

Where can negative selection of thymocytes occur? Mediated by which cells?

Answer 36

In cortex or medulla Cortical epithelium cell Medullary epithelium cell Thymic bone marrow-derived cell

Question 37

What occurs if there is strong TCR signaling in negative selection of thymocytes?

Answer 37

Self-reactive thymocyte dies

Question 38

What is thymocytes emigration induced by?

Answer 38

Sphingosine 1-phosphate receptor, S1PR1 After 3 - days n the medulla, CD4 and CD8 T cells upregulate SIP1 and exit the thymus into the blood

Question 39

What does AIRE do?

Answer 39

Controls or regulates expression of certain self peptides

Question 40

Where is AIRE expressed?

Answer 40

Expressed in the medulla of the thymus

Question 41

Affinity model of T-cell positive and negative selection

Answer 41

Positive and negative selection is though to hinge on the strength of self-peptide:MHC binding by the TCR Low-affinity interactions rescue the cell from death by neglect, leading to positive selection High-affinity interactions induce apoptosis and thus negative selection