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Infection and Immunity > Intro to T cell + TCR > Flashcards

Intro to T cell + TCR Flashcards

1
Q

What are T cells?

A

Thymocyte specific lymphoid cells

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2
Q

What did the discovery of T cells show?

A

Idea of cell mediated immunity - not just by Ab
Associated with T cells -
eg. in vivo experiment done showed Listeria cannot be killed just by T cells or just macrophages - need to be together to get good enough response -> strong protection

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3
Q

What is the specificity of T cells?

A

T cells work in pathogen specific manner

ie. way T cells work depends on the type of pathogen

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4
Q

List some examples how T cells work differently depending on the pathogen

A 
Killing Listeria (intracellular organism) requires T cells + macrophages 
Killing virally infected cells (obligate intracellular pathogens) by T cells - no other cell type needed
Killing parasite by T cells requires IgE + eosinophils as co-factors

Shows T cells have many different subtypes which allow different functions to be carried out

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5
Q

What are cytotoxic T cells + what is their function?

A

CD8+ T cells

Good at killing virally infected cells + killing some intracellular bacteria

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6
Q

What type of T cells are helper T cells?

A

CD4+ T cells

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7
Q

List the subtypes of CD4+ T cells + their function

A

Th1 - can activate infected macrophages (Eg. Listeria)
Help B cells make more Ab
Usually targeted against bact (intra/extracellular)

Th2 - Help B cells class switch type of Ab to make IgE
.˙. control helminth/parasite infection

Tfh - aids class switching B cells

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8
Q

What is the function of suppressor T cells?

A

Important in controlling activity + certain responses

if not present, wouldn’t be able to eat anything non-human - .˙. need immune suppression

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9
Q

Compare B cells with T cells

A

B cells make Ab
Antigens that Ab deal with large, unprocessed proteins
.˙. B cells specialised @ attacking pathogens outside cells

T cells instead attack infected cells - gives restrictions on how they can work

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10
Q

How are T cells able to recognise Ag?

A

Done by Ag proteolysis inside infected cell
Pathogen proteins broken down into peptides + presented on surface by MHC 1/2 molecules

MHC-Peptide complex recognised by TCR

So able to recognise some feature pathogen that’s inside cell but from outside
This can’t be done by Ab ˙.˙ they recognise intact proteins

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11
Q

What are the specificities of the TCR?

A

Repertoire is huge - not germ-line encoded rearranged during somatic life
Each T cell has distinct receptor

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12
Q

What does recognition cause?

A

Activates signalling processes inside T cell -> diversity functional responses

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13
Q

What type of cells can T cells be?

A

Effector cells - short lived

Memory cells - long lived (nature T cell memory unknown)

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14
Q

What is specific about the recognition of MHC by TCR?

A

TCR only recognise peptides if in complex w/MHC = MHC - restriction
Demonstrated by Zinkernagal + Doherty MHC restriction
very tightly matched - if both MHC + peptide properly seen, signal response = recognition
If have wrong MHC (for presenting peptide or animal MHC) + correct peptide = no recognition or response
Correct MHC but wrong peptide = no recognition + response

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15
Q

What occurs if TCR recognition is not tightly regulated?

A

If don’t have dual Ag/MHC recognition = toxic shock syndrome

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16
Q

How does staphylococcus cause toxic shock syndrome?

A

Staphylococcal syndrome toxin-1 acts as super-antigen -> protein made by staphylococcus

Toxin 1 = bivalent protein
Can tightly bind MHC 2 + TCR .˙. bypasses need for peptide to be present
Can bind all MHC-II + TCR .˙. all T cells produce cytokines despite proper Ag processing not occurring

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17
Q

Where are T cells derived from?

A

Hematopoietic stem cells in bone marrow

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18
Q

What happens to T cells after they come out of bone marrow?

A

Migrate to thymus (immature when arrive) + mature there, retained there

Acquire T cell receptor by rearrangement
become either -> CD8+ cells (precursors to cytotoxic)
-> CD4+ (precursor to helper)

Then migrate to secondary lymphoid tissue (lymph nodes) as naive T cells -> here can interact w/ peptides presented on APC via MHC

Productive interaction w/ T cell expressing high affinity TCR -> Clonal selection + amplification of T cell

Selected + amplified cells leave lymph nodes + target infected tissues

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19
Q

Describe the TCR

A

Membrane bound
TCR’s all have different specificities
is ˙.˙ highly variable amino acid sequence of variable Ag-binding region

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20
Q

Describe the structure of the TCR

A

Structure is similar to Ig - have constant + variable region
Linked through disulphide bonds
Multi-chain molecules alpha beta major
hetero-dimer - 8 alpha, beta chains
Glycosylated
Variable region has pocket in it = Ag binding site; faces outside of extracellular surface of cell

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21
Q

What are the differences between TCR + Ab?

share common evolutionary origin

A

i. TCR - 1 binding site
Ab - multiple binding sites eg. IgM polymerised

ii. TCR not direct effector unlike Ab -> Ab can bind to target + simplify neutralise it

iii. TCR doesn’t bind to native Ag, only to processed peptides in cleft MHC-encoded proteins
depending on class1/2, length peptide can bind is distinct ˙.˙ generate peptides through different routes

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22
Q

What generates diversity in TCR?

A

Rearrangement of TCR genes generates diversity like Ig

eg. making alpha beta heterodimer TCR -> 2 complexes have alpha chain locus + beta chain locus

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23
Q

How does rearrangement of genes occur?

A

Germline material no complete genes exist for TCR alpha chain + beta chain
Begin with complexes of un-arranged genes
DNA rearranged to make genes which encode for intact TCR

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24
Q

What are the components involved in recombination of genes?

A

Alpha chain - variable region - 70/80 segments
J regions (short) - 60 segments
Constant region
All of these segments put together (1 of each) + fuse w/ c-alpha region

B chain - have D region - 2 completely different blocks
Larger range + slightly more complex

RAG genes + signalling sequences @ appropriate sites to allow looping out/ inversion intervening DNA @ jn to bring single V, D, J + C genes together

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25
Q

What occurs at the fusion point between V + J genes?

A

Insertion of non-coded bases, added by terminal transferase activity 1/2/3/ extra bases
Many proteins not productive (˙.˙. if insert 1 base it’s out of frame)
If in frame can increase diversity

26
Q

Is variation more important that in TCR or Igs?

A

TCR - as can make many distinct types of TCR = diverse amino acid sequence in CDR 3 loops - most of which make contact with presented peptide

27
Q

When are T cells immature and mature?

A

Immature when arrive as thymocytes into thymus
Mature when TCR selected + expressed CD4/CD8

BUT are still naive - s not yet been challenged by correct peptide
Happens after thymus in lymph node .˙. not clonally selected or amplified

28
Q

When do T cells become experienced? (as opposed to naive)

A

Once seen Ag - can respond to imminent threat or can lay down memory

29
Q

Where are T cells selected?

A

In thymus during development

30
Q

How do T cells get to the thymus?

A

Precursors travel from bone marrow + migrate to thymus down chemokine gradient

31
Q

What do T cells express in thymus?

A

Begin to express TCR + CD8+

32
Q

Why does T cell selection occur?

A

Remove self reacting receptors + receptors that won’t react

33
Q

What are the 3 groups that TCR’s are classified into?

A

Those that are potentially useful in interacting with foreign pathogens
(unknown what pathogens will be exposed to in life - so guess what may be useful and so don’t eliminate it)

Those don’t react with anything - produced because bases are inserted at junction between V + D/J
Makes out of frame - non-productive TCR

Those that are potentially harmful - react with self Ag (autoimmune diseases)
Stopped via selection in thymus

Last 2 types are removed

34
Q

How are the unwanted cells removed?

A

Cells that don’t express a productive TCR removed by DBD apoptosis
Cells don’t recognise MHC w/peptide bound strongly enough undergoes death by neglect (absence of survival signal)

-ve selection:
TCR with strong self-MHC + peptide recognition cell death is triggered (apoptosis)
-ve selection eliminates self reactive cells

35
Q

What is +ve selection?

A

Any cells can react to self peptide weakly to survive receive survival signals + MHC
Become mature (but still naive) + leave the thymus
migrate to peripheral lymphoid organs

36
Q

Where does alpha beta T cell selection occur?

A

Thymus

37
Q

What type of surface markers do newly arrived cells express in the thymus

A

CD4-, CD8-, CD44+, CD25+, CKIT
Double -ve cells
CD44 allows them to stick in the thymus + interact with receptors (triggers start of development process)
Don’t express TCR genes = early thymic progenitor cells (ETP)

38
Q

What occurs in the thymus to the ETPs?

A

Up-regulation of CD25 (IL-2 receptor) on these cells
IL-2 = T cell growth factor
Up-regulates recombinase genes - RAG1/2

Gene products of RAG1/2 required to rearrange TCR B locus (just like Ab) -> VDJ (c) recomb

At this stage unable to upregulate recombination of alpha locus

39
Q

What occurs after TCR-B rearranged?

A

It is tested to see if function
don’t immediately move onto rearranging A locus

Makes + expresses invariant alpha chain = pre-T alpha alongside TCR beta gene
If rearranged B-chain successfully pairs w/ invariant alpha chain, signals produced which cease rearrangement B chain + silences alternate allele (as have 2 alleles)

All above won’t occur if don’t have productive rearrangement B-chain ie. if have frame shift

40
Q

What occurs if pre-TCR forms?

A

Cell down-regulates CD25 (g-fx) + down-regulates CD44 (stops cell from sticking)
= DN4 cells (CD25-, CD44-)
Cells undergo proliferation + begin to rearrange TCR A-locus

Pre-TCR signals are made to start transcription genes for CD4 + CD8 - will be req to differentiate cells into CD4/CD8 T cells
Hence these are double positive cells as have both genes

Rearrangement TCR A + have fully productive TCR on cel surface + CD4/CD8 - just need to do selection

41
Q

What happens to the double positive thymocytes?

A

Migrate deep into thymic cortex
Self Ag presented to them - done by cortical thymic epithelial cells (cTECs) on cell surface,
cTECs present both MHC I/11

These interact w/ all T cells arriving
If get productive interaction (only the thymocytes interact with MHC1/2) - receive vital survival signals .˙. no apoptosis
Get selection of those cells = + ve selection

42
Q

How do cells differentiate into CD4/CD8?

A

Double +ve cells interact well with:
MHC II become CD4+ cells
MHC I become CD8+ cells

These will down-regulate other surface receptors eg. CD4 receptor + thus, prod. single +ve cell

43
Q

What occurs if a cell does not lose signal?

A

Continues to down-regulate CD8 + become a CD4+ single +ve cell

44
Q

What does +ve selection ensure?

A

That T cells have MHC affinity that’s weak for self peptides but not 0
Serves useful function in body
ie. cell able to interact w/ MHC + peptide complexes to effect immune response

45
Q

What occurs to the majority of thymocytes during +ve selection?

A

Vast majority die during this process
Takes few days
But +ve selection does not remove anything reacts strongly with MHC - done via -ve selection

46
Q

How does -ve selection occur?

A

Thymocytes survice +ve selection migrate to boundary of cortex + medulla in thymus
In medulla presented w/ self-Ag again on MHC complex by medullary thymic epithelial cells (mTECS)
Thymocytes react too strongly w/ self Ag receive apoptotic signal -> cell death

Potentially autoimmune cells are removed by process -ve selection

47
Q

What occurs after -ve selection?

A

Some are selected to become T reg cells

remaining cells exit thymus as mature, naive T cells

48
Q

What is -ve selection important for?

A

In central tolerance - serves to prevent formation self reactive T cells capable of inducing autoimmune diseases in host

49
Q

How is the thymus able to express self-Ag expressed in all tissues?

A

Theoretically thymus is a specialised organ + can only express self-Ag from thymus.
but negative selection only works if can express self-Ag from all tissues

Can do because mTECs express the T-fx - AIRE
Allows promiscuous expression of self Ag from all tissues of body on MHC-1
Any TCR recognises it strongly is given trigger to undergo apoptosis

50
Q

How are T cells that strongly recognise self-Ag presented on MHC-II -vely selected against?

A

Selected against by thymic DCs that can phagocytose mTECs

Enables the presentation of self-Ag on MHC-II molecules

51
Q

What happens after development of rearranged TCR?

A

T cells leave the thymus + relocate in the lymph nodes
Known as naive T cells until they encounter target Ag
Encounter occurs in 2’ lymphoid tissues - lymph nodes

52
Q

What occurs in lymph nodes?

A

Ag presented via APC
T cell interaction + experience? allows clonal selection + amplification
causes exit lymph tissue as ‘effector’ T cells + migrate to site of infection

53
Q

How do naive T cells migrate to the lymph node?

A

Produce chemokine receptor CCR7
Recognises molecule CCL21 - produced in high endothelial venules (HEV) - specialised blood vessels

Gradient CCL21 from lymph nodes
anything expressing CCR7 able to migrate towards those tissues along the gradient

Also recognise CCL19 because express CCR7
CCL19 produced by DC, also found in the lymph nodes
T cells go to lymph node + attracted to DC that’s presenting Ag

54
Q

How do T cells enter into the lymph node?

A

Dependent on chemokines + adhesion molecules
L-selectin on naive T cells induces rolling on endothelial surfaces as L-selectin binds weakly to blood vessel surfaces

Chemokine CCL21 recognition @ high conc causes actvn integrin - enhances binding ability to T cells

55
Q

What are lymph nodes, and how to T cells + DC arrive?

A

Highly specialised organs
DCs arrive through afferent lymphatics
T cells arrive through blood

56
Q

What is the function of lymph nodes?

A

Organise T cells + DC together into complexes trigger differentiation + clonal selection, amplification of T cells
Then leave

57
Q

What happens to naive T cells don’t encounter specific Ag in lymph nodes?

A

Naive t cells can make contact w/ thousands of DC in lymphoid tissue

Exit lymph node via efferent lymphatics
Re-enter blood circulation + continue circulating

If encounter specific Ag, cease to migrate + instead differentiate

If this did not occur, would not be able to continually survey what body is infected with.

58
Q

How are effector T cells guided to sites of infection?

A

Chemokines + newly expressed adhesion molecules
Ceases production L-selectin .˙. no longer homed into lymph nodes

Express VLA-4 recognises VCAM (Vascular endothelial adhesion molecule)
VCAM-1 upregulated @ site of infection (on vascular endothelium) - indicates inflammatory response

T cell sticks to peripheral endothelial cell + localised to infection site.

59
Q

What allows initial binding to potential targets?

A

Non-specific adhesion molecules - as need to check if has right MHC combo
If correct Ag/MHC combo - TCR signalling occurs which induces conformational change in adhesion proteins = strengthens binding

Process allows focused release toxic effector molecules
If not targeted, could get lots of tissue damage
Multiple layers control highly focused interaction

60
Q

What is the function of GD T cells?

A

Do same as AB T cells

Are membrane bound, heterodimer, Ag binding site

61
Q

What is different in comparison to AB T cells?

A

Less variability than conventional TCR, together w/ CD3:

May play role in innate immune response

62
Q

Where do GD T cells reside?

A

Peripheral sites - skin, lung, intestine, liver
mount immune response to frequently encountered PAMPs
eg. bact surfaces, inappropriately expressed phospholipid etc

Infection and Immunity (8 decks)

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