Exam 2 Lecture 7: T Cell Development

Question 1

Which organs are involved in T cell development

Answer 1

bone marrow, thymus, secondary lymphoid tissues (lymph nodes, spleen, GALT)

Question 2

Antigen presenting cells in the thymus

Answer 2

Thymus cortex: cortical epithelial cell,
thymocyte
Thymus medulla: medullary epithelial cell, dendritic cell, macrophage

Question 3

Where does T cell proliferation occur

Answer 3

T cell precursors proliferate extensively in the thymus, most die there as well

Question 4

What does double negative, double positive, single positive mean

Answer 4

DN: CD8- CD4-
DP: CD8+ CD4+
SP: CD8+ or CD4+

Question 5

What are the 5 major steps of T cell development

Answer 5

lineage commitment, receptor rearrangement, positive selection, CD4/CD8 subset commitment, negative selection

Question 6

T cell lineage commitment

Answer 6

Commit to be a T cell
Thymocytes express Notch1 which binds to Notch ligand on epithelial cells
Binding initiates gene transcription inside thymocytes

Question 7

What is the end product of receptor rearrangement and what are the steps

Answer 7

Determines γ/δ or α/β
α-chain rearrangement deletes the δ-chain genes
1. β-chain locus rearrangement: successful synthesis of β-chain allows production of pre-TCR that triggers proliferation and blocks b-chain rearrangement
2. pre-TCR checkpoint 1: pre-TCR consists of rearranged β-chain + pre-T-α-chain, signaling induces more proliferation and CD4/8 expression
3. proliferation and CD4/8 expression double positive
4. α-chain locus rearrangement

Question 8

Positive selection

Answer 8

Checkpoint #2
Occurs in cortical thymus epithelial cells
reward cells with function receptors that can receive moderate to strong binding from either MHC I or II
Non functional cells die

Question 9

CD4/CD8 subset commitment

Answer 9

1. Positively selecting TCR signals initially reduce both CD4 and CD8
2. All express CD4 regardless of signaling ligand (CD4+CD8low)
   2a. Cells that still express weak TCR signal block IL-7 signaling (and become CD4)
   2b. Cells that have no signaling become CD8
3. Transient expression of ThPOK leads to CD4, absence leads to CD8
   Leads to single positive cells

Question 10

Negative Selection

Answer 10

Occurs at any point during entire process by any cells
T cells that react too strongly with self antigens are deleted

Question 11

What stage of T cell development excludes the formation of gamma-delta T cells

Answer 11

-receptor rearrangement
-past checkpoint #1
-α-chain formation

Question 12

Which cells express Notch and Notch ligand

Answer 12

Thymocytes

Question 13

What does Notch signaling do for T cell precursors

Answer 13

Commits cells to be T-cells

Question 14

What are checkpoint #1 and #2

Answer 14

1: during receptor rearrangement after β-chain rearrangement, pre-TCR assembled
2: positive selection

Question 15

What does TCR signaling blockade of IL-7 signaling have to do with CD4/CD8 subset commitment

Answer 15

Cells that still express weak TCR signal block IL-7 signaling (and become CD4)
Cells that have no signaling become CD8

Question 16

What is AIRE and why is it important for negative selection

Answer 16

Found in medulla of thymus
Allows expression of proteins normally only found in (non immune) peripheral tissues

Question 17

Why do mutations in AIRE or deficiencies in Tregs lead to autoimmunity

Answer 17

Mutations in AIRE > APECED
Deficiencies in Treg > IPEX
T cells escape from thymus and attack body