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Immunology > 11. T Lymphocyte Development > Flashcards

11. T Lymphocyte Development Flashcards

1
Q

what is lymphopoiesis

A

the production of new lymphocytes in central lymphoid organs

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2
Q

In the thymus what helps differentiate T-lymphocytes

A

thymic hormones

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3
Q

what are thymocytes

A

lymphocyte in the thymus gland

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4
Q

what happens in different regions of the thymus (e.g. cortex vs medulla)

A

different stages of T cell development

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5
Q

match locations of T cells to their development stage

A

outer cortex = immature proliferating thymocytes
inner cortex = mature thymocytes undergoing selection

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6
Q

what makes up the thymic stroma

A

cortical epithelial cells and medullary epithelial cells

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7
Q

what are the key players in T-cell precursor apoptosis

A

macrophages in the thymus cortex and medulla

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8
Q

successive stages in thymocyte development are marked by status of ______ and changes in ______

A

TCR genes and TCR expression
Cell-surface molecule expression (CD3, 4 and 8)

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9
Q

what are the 2 distinct lineages of thymocytes

A

yd T-cells
aB T-cells: develop into CD4 and CD8 (most common)

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10
Q

stages in T-cell development and where they take place in the thymus

A
  1. Double negative (CD3- CD4- CD8-): sub capsular zone of cortex
  2. Double positive (CD3+ CD4+ CD8+): inner cortex
  3. Single positive: medulla
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11
Q

how many double negatives occur in T cell development

A

4

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12
Q

If a T cell does or does not proceed past DN2, what lineage does it become a part of

A

does not = yd T-cells
does = aB T-cells

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13
Q

what is notch signalling is notch signalling on and off

A

in the bone marrow = OFF
Early T-cell precursor = ON
B-selection = OFF

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14
Q

what is notch signalling essential for

A

T cell lineage commitment and early phases of thymocyte differentiation up to DN3

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15
Q

when does B-chain rearrangement happen in T cell development

A

Double negative 3 - VDJ recombination and B-selection happen

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16
Q

why is notch signalling turned off for common lymphoid progenitors in the bone marrow

A

allows cells that stay in the bone marrow to develop into B cells

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17
Q

characteristics of Double-Negatives - the earliest T cell precursors

A
  • have not yet rearranged TCR loci
  • don’t express CD4 or CD8
  • don’t express CD3
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18
Q

3 markers of Double-Negatives - how we know the T cell is at this stage

A
  1. c-KIT: receptor for stem cell growth factor
  2. CD44: adhesion molecule
  3. CD25: alpha chain of the IL2 receptor
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19
Q

what is the T-cell known as at each of the 4 double-negative stages

A

DN1: early T-cell precursor
DN2: Pro-T cell
DN3: small pre-T cell
DN4: large pre-T cell

20
Q

when does CD3 expression appear

A

between DN2 and DN3

21
Q

what makes the pre-T cell receptor

A

new B chain
Pre-Ta (surrogate chain)
CD3

22
Q

which proteins are important in T-cell commitment

A

notch and IL-7R

23
Q

important signalling proteins in T cell development and when they are active

A

Notch: DN1 to DN4
CD3: DN2 to single positive
IL-7R: DN1 to DN4, single positive

24
Q

what are the checkpoints of T-cell development

A
  1. TCRB rearrangement
  2. TCRa rearrangement
25
Q

why is the pre-TCR important

A
  • productive TCR B-chain rearrangement
  • signals for proliferation and maturation
  • suppresses further B chain rearrangement (allelic exclusion)
  • signals for TCR a chain rearrangement
  • induces development of CD4+CD8+ (DP)
26
Q

what is allelic exclusion

A

recombination shut down to prevent further recombination of the B-chain - prevents the thymocyte from producing more than one functional B-chain

27
Q

why are cells considered double-positive

A

both CD4 and CD8 are expressed

28
Q

what does expression of CD4 and CD8 initiate

A

rearrangement of a-chain locus in double-positive cells

29
Q

B-chain rearrangement happens before a-chain rearrangement. what are the specific stages at which these happen?

A

B-chain rearrangement: DN3
a-chain rearrangement: Double positive

30
Q

what are cTECs and mTECs

A

cTECs = cortical epithelial cells, express MHC II , roll in positive selection
mTECs = medullary epithelial cells, present antigens, roll in negative selection

31
Q

why do we have 4 attempts at B-chain rearrangement

A

because 2 clusters of each D and J gene segments for the B-chain

32
Q

what are the stages of gene rearrangement in aB-T cells

A
  1. Germaine gene configuration
  2. DB and JB rearrangement
  3. VB and DJB rearrangement - B chain produced
  4. surface expression of B-chain with surrogate a-chain, B-rearrangement stops, CD4/8 induction causes a-transcription to start
  5. Va and Ja rearrangement
33
Q

there are many rounds of a-chain rearrangement until…

A

positive selection or death

34
Q

what happens after an aB TCR becomes expressed on the T-cell surface

A

cells undergo positive and negative selection
those that fail either selection undergo apoptosis
those that pass selection lose either CD4 or CD8 and become single positives

35
Q

when do thymocytes interact with cortical epithelial cells

A

in the double positive stage

36
Q

characteristics of positive selection of T-cells

A
  • occurs in the thyme cortex
  • T-cells that are able to bind to self-MHC molecules in the thymus go onto mature
  • results in MHC restriction
37
Q

characteristics of negative selection of T-cells

A
  • occurs in the cortex and medulla
  • removes T cells whose TCR has high affinity for self-MHC with self-antigen
  • cells die by apoptosis in the thymus
  • results in self tolerance
38
Q

what will happen in T-cell selection based on T-cell receptor affinity for self peptides:self MHC

A

too little = no selection
just right = positive selection
too much = negative selection

39
Q

the role of cTECs in positive selection

A

DP tested by APCs or cTECs for the affinity of their T-cell receptor for the MHC molecules presenting antigen

40
Q

the role of mTECs in negative selection

A

SP in the medulla that bind to MHC molecules presenting antigens of mTECs or dendritic cells die by apoptosis

41
Q

what are the 3 possible fates of developing thymocytes in the thymic cortex

A
  1. cTEC receptor doesn’t bind peptide = death by neglect (apoptosis)
  2. cTEC receptor has moderate binding to peptide = positive selection - maturation to SP
  3. cTEC or APC has high binding to peptide = negative selection (apoptosis)
42
Q

different ways positive selection coordinates expression of CD4 and CD8 (+potential effector functions)

A
  1. normal MHC II expression = both CD8 and CD4 mature
  2. MHC II-negative mutant = CD8 matures
  3. mutant with MHC II trans gene expressed in cortical thymic epithelium = both CD8 and CD4 mature
  4. mutant with MHC II trans gene expressed that cannot interact with CD4 = CD8 matures
43
Q

what is AIRE

A

autoimmune regulator which enables presentation of tissue-specific self-antigens
important in central tolerance

44
Q

where does negative selection occur

A

the thymic cortex and medulla

45
Q

what induces thymic emigration of T-cells

A

signalling through the sphingosine 1-phosphate receptor

46
Q

characteristics of the pre-T cell receptor

A
  • inhibition of B chain gene recombination
  • proliferation of pre-T cells
  • stimulation of a-chain recombination
  • expression of CD4 and CD8
  • shut off of pre-Ta transcription
47
Q
A

Immunology (22 decks)

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