Module 7: T-Ontogeny

Question 1

When does T cell generation occur?

Answer 1

Neonatally/early in life

Question 2

What is thymic erosion?

Answer 2

The thymus begins to shrink after puberty and so does the production of T cells

Question 3

Explain the migration steps of thymocytes during development

Answer 3

1) Hematopoietic stem cells differentiate into common lymphoid progenitors in the bone marrow
2) Thymic precursors (double negative) are multipotent and enter the thymus through PSGL-1:P-selectin, CCR7:CCL19, and CCR9:CCL25 chemokine interactions
3) Migration to the cortex is mediated by CCR9:CCL25 chemokine interactions

Question 4

Describe the development T cells with γδ TCRs

Answer 4

1) Gamma then delta chain is rearranged
2) If rearrangement is successful, T cells leave the thymus as double negative T cells that do not recognize MHC-antigen complexes

Question 5

Describe the steps of development from DN1 to DN4 T cells

Answer 5

1) DN1 = entrance of multipotent precursors into thymus
2) DN2 = start of TCR beta chain rearrangement (by RAG1/2)
3) DN3 = rearranged beta chain is expressed with an invariant alpha chain to test if rearrangement was successful (pre-TCR)
4) cTECs present antigens on MHC molecules and if TCR signaling is received, cells survive and proliferation = DN4

Question 6

What are cTECs?

Answer 6

Thymic cortical epithelial cells, responsible for mediating positive selection

Question 7

What does successful rearrangement of the beta chain result in?

Answer 7

1) Closing of the other beta-chain allele (allelic exclusion)
2) TCR alpha-chain locus rearrangement
3) Rapid proliferation of DN4
4) Stimulated expression of CD4/CD8

Question 8

Describe the steps of development from DN4 to DP T cells

Answer 8

1) DN4 proliferate rapidly and undergo alpha-chain rearrangement to produce DP thymocytes (also express CD3)
2) DP thymocytes undergo positive selection - they must be able to recognize self-MHC molecules on cTECs (low/intermediate affinity is selected for)
3) Cells that survive commit to a SP pathway and migrate to the medulla via CCR7:CCL19 chemokine interactions

Question 9

What is different between alpha and beta chain rearrangement in T cells?

Answer 9

Alpha-chain is not subject to allelic exclusion
1) T cells can express 2 different alpha chains
2) If T cells fail selection, they can rearrange their other alpha chain locus

Question 10

Describe the process of negative selection in the medulla

Answer 10

1) mTECs and DCs show self-antigens to the T cells
2) High TCR signaling results in apoptosis/clonal deletion
3) Medium levels of TCR signaling results in Treg induction (FoxP3+, CD4+)
4) No TCR signaling results in complete maturation

Question 11

What are the 2 mediators of negative selection

Answer 11

mTEC (thymic medullary epithelial cells) and DCs (develop from the bone marrow)

Question 12

How do mTECs mediate negative selection?

Answer 12

The cells express AIRE (autoimmune regulatory element) which drives expression of tissue-specific antigens for presentation

Question 13

What does a deficiency in AIRE result in?

Answer 13

Severe autoimmunity (APECED)

Question 14

How do DCs mediate negative selection?

Answer 14

1) Licensed DCs have the ability to cross present antigens to CD8+ T cells
2) Do not express AIRE but hypothesized that mTECs either pass antigens to DCs or DCs phagocytose dead mTECs

Question 15

How do we know that negative selection is mediated by DCs?

Answer 15

Bone marrow transfers are sufficient to induce tolerance to allogenic transplants (i.e., between MHC-incompatible donors/recipients)

Question 16

What are the 3 models for how DP cells become SP?

Answer 16

1) Instructive model
2) Stochastic model
3) Kinetic signaling model

Question 17

What is the instructive model?

Answer 17

1) Engagement with one antigen/MHC complex results in downregulation of the other
2) Both are tested, and whichever interaction provides a strong signal “wins”

Question 18

What is the stochastic model?

Answer 18

1) Random downregulation of either CD4 or CD8
2) CD4+ or CD8+ cells are then tested for their ability to recognize MHC II and MHC I, respectively
3) If weak signaling = die by apoptosis
4) If successful = commitment to CD4+ or CD8+

Question 19

What is the kinetic signaling model?

Answer 19

1) TCR first engages with MHC II and CD8 is downregulated first
2) CD4+ cell is then tested for signaling ability
3) If signaling is weaker = IL-7 and Runx3 expression inhibits CD4+ and induces CD8+
4) If signaling is stronger = ThPox is upregulated, resulting in continued downregulation of CD8+, and increased CD4+ expression

Question 20

What is the paradox of alloreactivity?

Answer 20

Antigen-specific T cell responses are restricted to self-MHC but T cells can also react to foreign MHC in an antigen-independent matter

Question 21

What is the graft vs host disease?

Answer 21

The graft treats the host as foreign and attacks it