L12, T cell development and activation

Question 1

recap: where do T cells develop?

Answer 1

in the thymus

Question 2

where do the T cells originate from?

Answer 2

bone marrow

Question 3

T cells that travel from the bone marrow into the thymus are known as …

Answer 3

thymic settling precursors

Question 4

precursor cells are not committed to …

Answer 4

becoming a T cell yet

Question 5

what are developing T cells called?

Answer 5

thymocytes

Question 6

what do microenvironments provide within the thymus?

Answer 6

membrane-bound and soluble signals that regulate maturation during the development of T cells

Question 7

what are the two phases of T cell development?

Answer 7

1. early thymocyte development
2. selection events

Question 8

early thymocyte development is …

Answer 8

largely TCR-independent

Question 9

what are the 3 specific events during early thymocyte development?

Answer 9

1. commitment of hematopoietic precursors to the T cell lineage
2. initiation of antigen receptor gene rearrangements (TCR)
3. expansion of cells that successfully rearrange one of their TCR gene = beta selection

Question 10

what are double negative stages? and how many are there?

Answer 10

absence of expression of CD4 and CD8 molecules
4 double negative stages

Question 11

what markers can be used to identify different DN stages?

Answer 11

1. c-Kit: also known as CD117 = receptor for stem cell factor
2. CD44: adhesion molecule
3. CD25: IL-2 receptor alpha chain

Question 12

what do DN1 thymocytes do?

Answer 12

migration to thymus

Question 13

DN1 markers = …

Answer 13

c-Kit++CD44+CD25-

Question 14

what do DN2 thymocytes do?

Answer 14

rearrangement of TCR, sigma- and beta chain; fully committed to T-cell lineage

Question 15

DN2 markers = …

Answer 15

c-Kit++CD44+CD25+

Question 16

what do DN3 thymocytes do?

Answer 16

make a major decision: join the ysigma or alpha-beta T cell lineage / expression of pre-TCR; beta-selection

Question 17

what do most of the ysigma T cells do?

Answer 17

leave the thymus as mature DN y-sigma T cells

Question 18

DN3 markers = …

Answer 18

c-Kit+CD44-CD25-

Question 19

formation of the pre-TCR involves …

Answer 19

1. a successfully rearranged beta-chain
2. pre-T alpha-chain
3. CD3 molecules

Question 20

what does signaling through the pre-TCR trigger?

Answer 20

a cascade of events that starts with the maturation of DN3 into DN4

Question 21

DN4 markers =…

Answer 21

c-Kit(low/+) CD44-CD25-

Question 22

what is the function of DN4 thymocytes?

Answer 22

proliferation, allelic exclusion of beta chain locus; alpha chain locus rearrangement begins; becomes DP thymocyte

development of CD4+CD8+ double-positive stage

Question 23

selection events are ….

Answer 23

largely TCR-dependent

Question 24

double positive thymocytes are characterized by …

Answer 24

the expression of both CD4 and CD8 markers

Question 25

what percentage of cells do DP contribute to in the thymic cortex?

Answer 25

80%

Question 26

what do DP thymocytes express at their surface?

Answer 26

a fully mature alpha-beta TCR/CD3 complex

Question 27

what are the distinct selection processes that DP thymocytes go through?

Answer 27

positive and negative selection

Question 28

positive selection = ...

Answer 28

selection of thymocytes bearing receptors capable of binding self-MHC molecules (MHC restriction)

Question 29

negative selection = ...

Answer 29

selection against thymocytes bearing high-affinity receptors for self-MHC/peptide complexes (self tolerance)

Question 30

what are self-antigens presented by?

Answer 30

cortical thymic epithelial cells (cTECs), to mediate positive selection

Question 31

what triggers maturation of T cells?

Answer 31

low/intermediate affinity interaction between the TCR and MHC

Question 32

what does maturation of T-cells trigger?

Answer 32

commitment to CD4+ or CD8+ single-positive (SP) T cell lineages

Question 33

how many T cells are not selected?

Answer 33

about 90-96%

Question 34

what are the 3 different models of T-cell lineage commitment?

Answer 34

1. instructive model 2. stochastic model (random) 3. kinetic signalling model

Question 35

what other lymphocyte types can DP thymocytes commit to?

Answer 35

1. NKT (natural killer T cells) 2. intraepithelial lymphocytes (IEL) - most of which are CD8+ 3. Regulatory T cells (TREG) - another CD4+ subset different from CD4+ Th cells

Question 36

what transcription factor do medullary thymic epithelial cells express?

Answer 36

autoimmune regulator - allows cells to express tissue-specific antigens (TSA) from all organs

Question 37

what do high affinity TCR-MHC/peptide interactions result in?

Answer 37

negative selection = clonal deletion

Question 38

what are the 3 signals in T cell activation?

Answer 38

1. TCR signaling 2. costimulatory interaction 3. cytokine signaling

Question 39

What happens with T cells in order to mount a response that is appropriate against a given pathogen?

Answer 39

T cells can be polarized towards different subsets with specialized functions

Question 40

what are the 3 factors influencing polarization?

Answer 40

1. polarizing cytokines 2. master gene regulators 3. effector cytokines

Question 41

What kind of pathogens are detected in type 1 response (Th1 polarization)?

Answer 41

intracellular pathogens inducing cell-mediated immunity (most viruses, some bacteria and fungi)

Question 42

what happens in the type 2 response (Th2 polarization)?

Answer 42

pathogens inducing humoral immunity, particularly extracellular parasites

Question 43

what is the polarizing cytokine in the type 1 response?

Answer 43

IL-12

Question 44

what is the polarizing cytokine in the type 2 response?

Answer 44

IL-4

Question 45

what are the master regulators in Type 1 response?

Answer 45

STAT4 --> T-Bet

Question 46

what are the master regulators in Type 2 Response?

Answer 46

STAT6 --> GATA-3

Question 47

what is the effector cytokine produced in Type 1 response?

Answer 47

IFN-y

Question 48

what are the effector cytokines produced in Type 2 response?

Answer 48

IL-4, IL-5, IL-13

Question 49

what are the distinct microenvironments in the thymus?

Answer 49

1. subscapular cortex 2. cortex and cTECs 3. Corticomedullary junction 4. Medulla and mTECs

Question 50

description of DN1 development

Answer 50

migration to thymus

Question 51

description of DN2 development

Answer 51

TCR gamma, sigma, and Beta-chain rearrangement; T-cell lineage commitment

Question 52

what do DN3 thymocytes express?

Answer 52

pre-TCR

Question 53

description of DN4 development

Answer 53

proliferation, allelic exclusion of beta-chain locus; alpha-chain locus rearrangement begins; becomes DP thymocyte