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Infection and Immunity > 11 B and T cell development and differentiation > Flashcards

11 B and T cell development and differentiation Flashcards

1
Q

what must be ensured in B and T cell development

A

do not respond to self-antigen (negative selection)

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2
Q

what must be ensured in T development

A

T cells can respond to MHC (positive selection)

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3
Q

what are the different receptors on the T cell surface

A

CD4 and CD8

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4
Q

Lymphocyte binding repertoire

A

Because of the myriad of microbial challenges-antigen binding repertoire has to be extensive
Self-binding must occur during the process of the generation of diversity

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5
Q

why is there mechanisms to minimise lymphocyte binding repertoire

A

devastating consequences (i.e. autoimmunity)

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6
Q

what are the two tolerance to self

A

Central Tolerance

Peripheral Tolerance

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7
Q

what does central Tolerance concern

A

immature T and B cells at the point of differentiation where

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8
Q

Central Tolerance effect

A

> B cells have a newly former Ig at surface forming a BCR

> Pre-T cells differentiate intoCD4and CD8

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9
Q

Central Tolerance - mechanisms

A

> clonal deletion or inactivation of the cell

> wide range of self-antigens expressed in primary lymphoid tissue to aid this process

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10
Q

what does peripheral Tolerance relate to

A

mature T cells after they have left the primary lymphoid tissue

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11
Q

Peripheral Tolerance effects

A

> Clonal deletion and anergy but others too e.g. suppression

> Antigens expressed in tissues

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12
Q

B cells develop in bone marrow then migrate to lymphoid tissues

A

bone marrow
Immature B-cells proliferate
Differentiate and develop antigen receptors (surface Ig)
Self-reactive cells eliminated
Bone marrow stromal cells (i.e. connective tissues) interact and provide factors (cytokines) necessary for development to eliminate self-reactive cells

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13
Q

what do B cells need to be able to function

A
  1. Encounter antigen
  2. Recognise it
  3. Respond to it
  4. Differentiate - effector cell
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14
Q

Recognise it - B cells

A

> As the B-cell only has one immunoglobulin receptor it can recognise
Therefore, there is only going to be a few antigens that B cell will recognise

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15
Q

Respond to it - B cells

A

> response driven by support given to B cell in secondary lymphoid organs

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16
Q

B cell tolerance

A

If the B cell receptor on the immature B cell detects antigens in the bone marrow it is deleted

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17
Q

when are B cells made

A

produced throughout your life

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18
Q

why is there a need for mechanisms to stop self recognition in B cells

A

As gene rearrangement occurs (which defines the antigen specificity) there is a need for mechanism to stop self recognition

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19
Q

what does an immature B cell express

A

surface IgM

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20
Q

what does a mature B cell express

A

surface IgD+ IgM

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21
Q

how do B cells generate in the bone marrow

A

B cell precursor rearranges immunoglobulin genes

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22
Q

what happens in negative selection in the bone marrow

A

immature B cell bound to self cell surface antigen is removed from repertoire

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23
Q

when do B cells migrate to the peripheral lymphoid organs

A

mature B cell bound to foreign antigen is activated

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24
Q

how are plasma and memory cells

A

activated b cells give rise to plasma cells and memory cells
antibody secretion in bone marrow and lymphoid tissue and memory cells in lymphoid tissue

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25
Q

what do the outcomes of developmental routes for B cell depend on

A

4 possible outcomes for a B cell which depend on the types and strength of interactions with antigens in the bone marrow

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26
Q

Developmental routes for B cell

A

4 possible outcomes

  • Deletion
  • Receptor editing
  • Anergy
  • Mature B cell
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27
Q

what happens if during B cell development recognises self

A
  1. Recognises self antigens
    - Deletion (very strong binding)
    - Receptor editing (but v early in development process)
    - Anergy (if it is a weak binding – leads to suppression of cells)
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28
Q

what happens if B cell does not recognise self antigens

A

Mature B cell

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29
Q

B cell DELETION

A

multivalent ligands have to be bound
- Use anti-IgM experimentally - cells die by apoptosis
As a mature B cell is activated by the same ligands - this process only works before they mature
- B cell is now expressing IgD on their surface

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30
Q

what does immature B cell express

A

IgM

31
Q

RECEPTOR EDITING

A

If IgM is bound by antigen in bone marrow immediate elimination (deletion) is NOT the only outcome
Cell can produce a new receptor by editing existing light chain gene
There is an interval between antigen recognition and apoptosis where cell can be rescued

32
Q

effect of receptor editing

A

results in deletion or displacement of old light chain gene with a new one

33
Q

INACTIVATION (Anergic)

A

If the immature B cell encounters monovalent molecule the cell is inactivated (ANERGIC)
These cells lose their expression of surface IgM
Mainly express IgD, but are released from bone marrow

34
Q

Peripheral Tolerance silencing

A

There is a need to silence cells in the periphery e.g. to liver/kidney antigens
Cells can be deleted or anergised (made silent)

35
Q

valency of antigens

A
  • Multivalent

- Monovalent

36
Q

multivalent

A

(several sites at which attachment to antigen can occur) = able to be deleted in the periphery

37
Q

monovalent

A

(one site at which attachment to antigen can occur) = able to be made anergic (silent)

38
Q

where does clonal deletion occur

A

in bone marrow or periphery

39
Q

where does anergy occur

A

in bone marrow or periphery

40
Q

Thymus

A

Bi-lobed organ which sits above the heart

2 compartments-cortex and medulla

41
Q

thymus cortex

A

Cortex-outer compartment has densely packed immature thymocytes (proliferate here) 95-99% will die

42
Q

thymus medulla

A

more sparsely populated-subset of mature thymocytes on the way out

43
Q

what is within the thymus

A

stromal cell network-epithelial cells, dendritic cells and macrophages interact with thymocytes

44
Q

what do thymic epithelial cells form

A

network around developing thymocytes

45
Q

Role of Thymus - Thymectomize

A

dramatic reduction in T cells

46
Q

DiGeorges syndrome (humans) in mice

A

nude mice -born with no thymus –no T cells

47
Q

Scid mice defect

A

have thymus but lymphocyte defect-no T cells
Bone marrow stem cells from nude mouse gives T cell progenitors
So transplanted T cell progenitors can use the normal thymus to develop fully

48
Q

Nude mouse

A

No thymus but normal T cell progenitors
Thymic architecture from SCID mouse gives a site for T cell progenitors to develop
SO existing T cell progenitors can use transplanted thymus to develop fully

49
Q

Maturation of T cells effect

A

T cells mature the antigenic diversity of capability to recognise ag occurs by random mutation

50
Q

what happens to maturing T cells

A
  • As they express Ag binding receptors (T cell receptor) selection occurs
  • Cells positively selected by recognising self MHC (on epithelial cells of thymus)
  • Negatively selected if recognise self in MHC
51
Q

how do T cell progenitors develop in bone marrow and migrate to the thymus

A

T cell precursor rearranges its T cell receptor genes in thymus

52
Q

what happens in positive and negative selection in thymus

A

immature T cells that recognises self MHC receive signals for survival
those that interact strongly with self antigen are removed from repertoire

53
Q

when do mature T cells migrate to the the peripheral lymphoid organs

A

mature T cells encounter foreign antigens in the peripheral lymphoid organs and are activated

54
Q

when do activated T cells migrate to sites of inflammation

A

activatedT cells proliferate and migrate to peripheral sites to eliminate infection

55
Q

where do most cells die

A

in the thymus

56
Q

what happens to single positive cells

A

exported to the periphery from the thymus

57
Q

when do T cell Surface markers change

A

change during development

58
Q

what happens when cells enter thymus-negative

A

Proliferate and express CD-2 but CD4 and CD8 negative

- “double negatives”

59
Q

what are the double positive cells where are they exported to

A

CD4+8- and CD4-8+ exported to periphery

60
Q

Need to recognise self MHC

A

1st Phase is positive selection where cells that recognise self MHC peptide complex are selected for survival this happens on double positive cells
If TCR does not recognise self MHC it will die by programmed cell death

61
Q

Positive selection

A 
Not only selects for MHC reactive cells
Also co-ordinates the expression of CD4 or CD8 thus determining the type of effector function
Initially expresses both CD4 and CD8
Selection based on whether react to class I or class II MHC in thymus
62
Q

why do CD4 and CD8 cells require different programming

A

different effector functions

63
Q

what are cortical epithelial cells needed for

A

cells are critical for positive selection

64
Q

what do cortical epithelial cells make close contact to

A

developing thymocytes

65
Q

when are CD8+ T cell matured

A 
transgenic receptor recognises MHC class 1
immature CD4+8+ double-positive T cells
66
Q

when are CD4+ T cell matured

A 
transgenic receptor recognises MHC class 2
Immature CD4+8+ double positive T cells
67
Q

Peptides in MHC affect positive selection

A

Ensures developing T cells have TCR which doesn’t react to self-antigens from rest of body
But T cells have to have TCR which will interact with self MHC
Delicate balance of affinity

68
Q

why are many self peptides expressed in thymus

A

due to the action of the AIRE (autoimmune regulator protein)

69
Q

NEGATIVE SELECTION

A

If T cell encounters Antigen in the thymus it DIES

- many self antigens expressed either from circulation or thymus itself

70
Q

what can demonstrate negative selection

A

Male ag can demonstrate this

Transgenic mouse with TCR for male antigens

71
Q

Key question How can MHC peptide/TCR ligation lead to BOTH positive and negative selection

A

2 hypotheses

  • Avidity –i.e the strength of the binding and no receptors engaged
  • Differential signalling-i.e nature of the signal different
72
Q

what is needed for a reaction

A

Bottom line is need 2 signals, TCR plus co-stimulation
Co stimulatory alone
MHC alone
They’re not enough on own need both

73
Q

what happens if only co stimulatory or MHC alone

A

No second signal = anergy

Infection and Immunity (29 decks)

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