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Immunology > Lec 14: T cell DADM > Flashcards

Lec 14: T cell DADM Flashcards

1
Q

Do all naive T cells recognize self MHC-peptide complexes?

A

yes, they weakly recognize self-MHC

preferentially bind foriegn antigen but need to bind self MHC for survailence (whcih is part of the +ve selection process)

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2
Q

breif overview of the process of early thymocyte development

A

very early thymocyte development occurs in the bone marrow

then cells migrate to the thymus for further development

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3
Q

development of thymocytes in the thymus

talk about the different stages

A

positive/ negative selection stages to become single positive cells (these still have CD3)

then a final screening to remove autoreactive cells

they are then released into the peripheral bloodstream`

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4
Q

blerb about recombination of TCR gene segments to produce ab or gd T cells

A

occurs during the dn stage

TcRb rearrangements are one of the first to take place, and most likely to be productive

because of this, TcRab outsome are more likely thatn TcRgd (except in fetal development)

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5
Q

b-selection in DN thymocyte development

A

DN thymocytes undergo b-selection resulting in proliferation and differentiation

  • > allelic exclusion ensures only one b-chain is rearranged. This is because we only want to express one beta chain
  • > if rearrangement fails, can try again with the second

a successfully produced b chain is paried with the pre-Ta chain

  • > a 33kDa protein surrogate for real TcRa chain
  • > allows for formation of a pre-TcR complex (with CD3 proteins) and numerous signaling events
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6
Q

DP stage of thymocyte development

A

after b-selection has occured, thymocytes are at the DP stage

  • > Functional TcRa chain replaces surrogate pre-TcRa
  • > the cell still expresses both CD4 and CD8
  • > Positive and negative selection occurs, yielding mature SP T cell
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7
Q

The affinity model of thymocyte selection

A

based on the strength of interaction between the TcR and self-MHC complexes

the stronger it binds, = negative selection

90% of cells fail to recognise self-MHC peptide complexes = death by neglect

In the stochastic overlap, selection towards Treg, represses responses towards self MHC antigen.
-> slightly less = naive T cell

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8
Q

Positive selection

A

intermediate affinity for MHC-peptide complex

thymocyte survival

resultrs in MHC restriction

COmmitment to either the CD4+ or CD8+ T cell lineage

most cells (90-95%) fail positive selection and do not receive need survival signals

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9
Q

negative selection

A

also known as clonal deletion

linits recognition of self

results in self-tolerance

skew cells to alternative factes, such ad Treg cells differentiaiton

less than 5% of thymocytes undergo clonal deletion

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10
Q

MTECS and negaive selection

A

MTECs have a uniqe TF AIRE which allows them to express TRA’s. These cells like to share antigen with DCs to aid in negative selection

allows new T cells to be safely screened in the thymus

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11
Q

Positive and negative selection ocurs in discrete thymic microenvironments

A

cortex and the medulla of the thymus provide microenvironments that coordinate a spatial and temporal segregation of thymocyte selection

Positive selection of ‘mainstream’ as T cells is sontingent on permissive interactions with a single APC type -> namely the cortical thymic epithelial cells (cTECs)

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12
Q

why are cTECs special

A

they have different proteasomes

different proteasomes = different peptides

cTECs have a proteasome that allows them to have the largest range of peptides

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13
Q

purpose of positive selection

A

makes sure that T cells bind a broad range of MHC-peptide complexes

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14
Q

Purpose of negative seleciton

A

negative selection (central tolerance) ensures self-tolerance

clonal deletion remains the best proven and most common method of tolerance induction in the thymus

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15
Q

clonal arrest

A

autoreactive T cells are prevented from maturing further

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16
Q

clonal anergy

A

autoreactive T cells are inactivated

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17
Q

clonal editing

A

second/thrid chance at rearranging a non-self-reactive TcRa gene

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18
Q

purpose fo the medulla and self tolerance

A

the medulla serves a crucial function for self tolerance induction
-> moreover disruption fo the 3D srchitecture of the medulla results in spont manifestations of autoimmunity

the medulla is a mosaic of self antigen

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19
Q

Tonic TcR signalling

A

T cells are selected based on the strength of interaction between the TcR and self-MHC complexes

resting T cells display a range of affinity for self, which generates a scale fo tonic signalling in vivo. -> engagesd but recognition is not sufficient to drove a response.

sub-threshhold tonic signals do not activate T cells, rather promote lymphocyte survial and modulated their function.

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20
Q

Relevance of CD5 for T Cells

A

more CD5 = stronger binding to self MHC peptide complexes

CD5 expression levels on SP thymocytes are thought to reflect the signalling intensity of the positively selecting TcR-MHC interaction
-> tuned CD5 levels persist on mature peripheral T cells as a footprint of thymic selection

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21
Q

what does re-exposure of mature T cells to their positively selecting pepetide(s) for

A

is necessary for homeostasis through continual tonic TcT stimulation

22
Q

CD5 in models of infection

A

CD5 hi Tcells for response to pathogens, CD5 high can outcompete
-> they react more strongly and are selected for because of the better immune response

biased T cell selection towards strongly self-reactive clones endows them with a homeostatic advantage and a head start in anti-pathogen responses

23
Q

how many signals are responsable for T cell activation

A

3 signal hypothesis

24
Q

Signal 1 of T cell activaiton

A

antigen-specific TCR engagement

25
Q

Signal 2 of T cell activation

A

contact with costimulatory ligands

26
Q

Signal 3 of T cell activation

A

cytokines direct T cell differentiation into effector cell types

  • IL 2 has autocrine actions for T cells
  • BInding IL 2 induces T cell proliferation during activaiton stages
  • Polarizing cytokines promote T cell differentiation into specific subsets
27
Q

Immunmological synapses

A

cSMAC

pSMAC

interactions can be as long as 3-4 hours

28
Q

cSMAC

A

central supramoleculer activating complex

TCR/MHC peptide complexes and co-recpetores centralize

29
Q

pSMAC

A

peripheral supramolecular activaitng complex

adhesion molecules. bound ligands peripherally localize

30
Q

positive costimulatory receptors

facilitate actiaviton

A

CD28 and ICOS

31
Q

CD28

A

44kDA glycoprotien expressed on the majority of T cells
Markedly enhances TCR induced proliferation and survival
binds to CD80 and CD86 expressed by APCs, involved in initial activation

32
Q

ICOS

A

inducible costimulator, binds ICOS-ligand on activated APCs
expressed on memory and effector T cells
= actrivation

33
Q

Negative costimulatory receptors

help turn activaiton off

A

CTLA-4 (CD152)

PD-1 (CD279)

34
Q

CTLA-4 (CD152)

A

induced within 24 hours after activaiton, peaks 2-3 days post-stimulation

binds to CD80/86 with higher affinity than CD28

puts the brakes on

35
Q

PD-1 (CD279)

A

PD-1 may help to mediate T cell tolerance in non-lymphoid tissues

inhibition

36
Q

T cell anergy

A

clonal anergy results if a costimulatory signal is absent

helps provide tolerance, especially in the periphery

if only MHC-peptide signal is recieved, cell is rendered non-responsive

anergic cells cannnot respond to subsequent challenge, even in the presence of costimulation

BLockade of CD28-CD80/86 interaction can render naive T cells anergic

this essentially resets the threshold for activation so high that it will never activate even with costimulation

37
Q

T cell differentiation

A

depends on interactions between APC and T cell

PRR signalling influences APC adn T cell interactions

Polarizing cytokines from APC or surroundng milieu influence T cell differentiation

T cells aquire an effector state
-> not fixed, T cells can be repolarized under the right conditions

38
Q

give an example of T cell differentiation

A

on the final

Naive CD4+ T cell -> Il-12 and IFNg triggers TF T-bet to induce differentation into a Th1 cell

Secretion of IFNg and TNF then can lead to machophage activation and inflammation

39
Q

T-bet

A

is a TF that promotes differentiation to a Th1 cell

40
Q

Importance of T cell differentiation

folicular Th cells

A

follicular helper T cells are CD4+ T cells that bprovide help to B cells
-> CD40L-CD40 interactions and the release of cytokines

CD4+ T cells can also helop mediate the initial generation of antiviral CD8+ T cells effector responses

41
Q

T helper cells contribute to the character of inflammatory responses in the tissue

example with Th1 cells

A

inflammatory = Th1 -> IFNg and Th17

CD4 indcution to cytotoxic cells
-> kill infelced APC’s

42
Q

T cell DC interactions and activation is a two way street

A

T helper cells can directly activate DCs

memory T cells can activate DCs and bypass the need for PRR activated costimulatory signals

Enhances innate immunity
-> is substantialy quicker and more effective that PRR-triggered responses alone

thus, memory cells can make the innate immune responses more robust

43
Q

type of memory T cells

A

not all effector T cells have equal potential to form memory T cells

terminal T effector cells (short-lived)

Long-0lived Tem memory cells

Longest-lived CCR7+ Tcm central memory cells

Trm resident memory cell

44
Q

Longest-lived CCR7+ Tcm central memory cells

A

reside in and traffic between secondary lymphoid organs

45
Q

Trm resident memory cell

A

reside in epithelial barrier tissues, the first site of antigen during an infection

46
Q

How are T cells selected in the thymus

A

write out a long answer response

47
Q

what is central tolerance and how is it achieved

A

Central tolerance, also known as negative selection, is the process of eliminating any developing T or B lymphocytes that are reactive to self. Through elimination of autoreactive lymphocytes, tolerance ensures that the immune system does not attack self peptides

mTECs and cTECs

48
Q

What is tonic TcR signalling, and what is the purpose of it

A

???

49
Q

What signals are required to activate a naive T cell? what happens if a key signal is absent?

A

???

50
Q

Make a table discussing the phenotype and function of

A 
Th1 cells
Th2 cells
Th17 cells
Treg cells
Tfh cells

Immunology (23 decks)

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