Lecture 14/15 T Cell Development Positive and Negative Selection

Question 1

Where does Class II processing Occur?

Answer 1

In acidic endosomes with Cathepsins S and L being the most important in proteolytic cleavage of peptides.

Question 2

CLIP

Answer 2

Class II associated invariant chain peptide prevents other peptides from binding class II.

Question 3

Why is invariant chain important?

Answer 3

Invariant chain prevents premature binding of peptides to Class II; binds to alpha and beta chains w/clip

Question 4

What enzyme cleaves Invariant chain?

Answer 4

Cathepsin S

Question 5

Class I (exogenous or endogenous)

Answer 5

endogenous

Question 6

Class II (exogenous or endogenous)

Answer 6

exogenous

Question 7

Invariant chain (Ii) (exogenous or endogenous)

Answer 7

exogenous; Ii binds to MHC II and keeps peptides from binding prematurely

Question 8

Lysosomal hydrolases (exogenous or endogenous)

Answer 8

exogenous; endosome and lysosome fuse;

Question 9

TAP1/TAP2 (exogenous or endogenous)

Answer 9

endogenous (associated with Class I only)

Question 10

Transport of vesicles from the ER to the golgi (exogenous or endogenous)

Answer 10

Both Class I and Class II MHC are made in the ER; both MHC II and I are both processed by the golgi

Question 11

Proteosomes (exogenous or endogenous)

Answer 11

MHC I; endogenous

Question 12

phagocytosis (exogenous or endogenous)

Answer 12

exogenous

Question 13

calnexin (exogenous or endogenous)

Answer 13

endogenous Chaperone for MHC I stabilizes class I

Question 14

CLIP (exogenous or endogenous)

Answer 14

exogenous MHC II; associated with invariant chain

Question 15

Tapasin (exogenous or endogenous)

Answer 15

endogenous

Question 16

In what organ to T Cells mature?

Answer 16

Thymus. Thymocytes originate from the bone marrow

Question 17

What are the two different T cell lineages?

Answer 17

ab vs gd

Question 18

EBF, E2A and Pax 5 are the important transcription factors for a progenitor cell to commit to B cell development. What transcription factor is important for T cell commitment?

Answer 18

Notch-1

Question 19

Thymic Cortex

Answer 19

contains cortical epithelial cells; immature thymocytes

Question 20

Thymic medulla

Answer 20

contain medullary epithelial cells; mature thymocytes

Question 21

Nude mouse

Answer 21

Defect in cortical epithelium, so thymus doesn’t develop

Question 22

SCID

Answer 22

Severe combined immunodeficiency caused by defect in genes that encode for RAG1/2; VDJ recombination can not occur.

Question 23

DN1

Answer 23

Express CD44 and Kit (Reacts w/SCF)

Question 24

DN2

Answer 24

Express CD44 and now CD25, begin to rearrange b chain of TCR (Db to Jb) become CD44’˚

Question 25

DN3

Answer 25

CD44'˚, Kit'˚, CD25 continue to rearrange b chain (Vb to DJb) and pair with preTalpha

Question 26

DN4

Answer 26

CD44-, CD25-, Pre-T Cell receptor complex w CD3 allows cells to proliferate and to block further b-chain rearrangement.

Question 27

Where does positive selection occur?

Answer 27

Deep cortex; with interaction with thymic cortical epithelial cells expressing MHC interact with DP cells- positive selection takes place.

Question 28

What is the first checkpoint in thymocyte development?

Answer 28

B chain rearrangement; preTalpha signaling; and CD4/CD8 at double negative

Question 29

Positive Selection

Answer 29

Takes place in the Cortext; double positive thymocytes receive survial signals after interacting with specialized APCs in the thymus - Thymic epithelial cells

Question 30

Positive Selection and Thymic environment

Answer 30

T cells are positively selected based on the MHC expressed by Thymic epithelial cells

Question 31

Where does positive selection occur?

Answer 31

By Thymic cortical epithelial cells in the Cortex

Question 32

3 Hypotheses to Explain Transition to single positive thymocytes

Answer 32

1) CD4 or CD8 is turned off randomly, no relation to TCR 2) Interaction between TCR, MHC I, and CD8 instructs cell to differentiate into CD8+ Class I restricted T cell. (and vice versa) 3) Interaction between TCR, MHC II and CD4 in a continuous signal instructs cell to differentiate into CD4+ class II restricted T cell, cell with CD8 gets an interrupted TCR signal and survives with IL-7 signals

Question 33

Where does negative selection occur?

Answer 33

In the medulla, bone marrow derived DCs and Macrophages are the most effective in mediating negative selection; cells that react strongly with self MHC: self peptide combinations are deleted during negative selection; results in tolerance

Question 34

Where do thymocytes become single positive?

Answer 34

Post-positive selection in the cortex.

Question 35

How does tolerance in the periphery occur?

Answer 35

Negative selection in secondary lymphoid organs, regulation by Treg,

Question 36

AIRE

Answer 36

Autoimmune Regulator; a transcription factor that induces the expression of many tissue specific proteins in the medulla on medullary thymic epithelial cells; mutations in AIRE lead to autoimmune disease against a variety of organ-APECED

Question 37

What role does Macrophages play in thymocyte apoptosis?

Answer 37

Macrophages phagocytose thymocytes that have experienced apoptosis.

Question 38

Scid/scid mouse

Answer 38

lack recombination machinery, cannot produce T Cell receptor

Question 39

Nu/nu mouse

Answer 39

lack thymus or thymic epithelial cells, cannot produce T Cells.

Question 40

Where are DN thymocytes found?

Answer 40

Subcapsular region