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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
What occurs at the fusion point between V + J genes?
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
Is variation more important that in TCR or Igs?
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
When are T cells immature and mature?
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
When do T cells become experienced? (as opposed to naive)
Once seen Ag - can respond to imminent threat or can lay down memory
29
Where are T cells selected?
In thymus during development
30
How do T cells get to the thymus?
Precursors travel from bone marrow + migrate to thymus down chemokine gradient
31
What do T cells express in thymus?
Begin to express TCR + CD8+
32
Why does T cell selection occur?
Remove self reacting receptors + receptors that won't react
33
What are the 3 groups that TCR's are classified into?
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
How are the unwanted cells removed?
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
What is +ve selection?
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
Where does alpha beta T cell selection occur?
Thymus
37
What type of surface markers do newly arrived cells express in the thymus
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
What occurs in the thymus to the ETPs?
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
What occurs after TCR-B rearranged?
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
What occurs if pre-TCR forms?
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
What happens to the double positive thymocytes?
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
How do cells differentiate into CD4/CD8?
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
What occurs if a cell does not lose signal?
Continues to down-regulate CD8 + become a CD4+ single +ve cell
44
What does +ve selection ensure?
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
What occurs to the majority of thymocytes during +ve selection?
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
How does -ve selection occur?
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
What occurs after -ve selection?
Some are selected to become T reg cells | remaining cells exit thymus as mature, naive T cells
48
What is -ve selection important for?
In central tolerance - serves to prevent formation self reactive T cells capable of inducing autoimmune diseases in host
49
How is the thymus able to express self-Ag expressed in all tissues?
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
How are T cells that strongly recognise self-Ag presented on MHC-II -vely selected against?
Selected against by thymic DCs that can phagocytose mTECs | Enables the presentation of self-Ag on MHC-II molecules
51
What happens after development of rearranged TCR?
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
What occurs in lymph nodes?
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
How do naive T cells migrate to the lymph node?
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
How do T cells enter into the lymph node?
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
What are lymph nodes, and how to T cells + DC arrive?
Highly specialised organs DCs arrive through afferent lymphatics T cells arrive through blood
56
What is the function of lymph nodes?
Organise T cells + DC together into complexes trigger differentiation + clonal selection, amplification of T cells Then leave
57
What happens to naive T cells don't encounter specific Ag in lymph nodes?
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
How are effector T cells guided to sites of infection?
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
What allows initial binding to potential targets?
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
What is the function of GD T cells?
Do same as AB T cells | Are membrane bound, heterodimer, Ag binding site
61
What is different in comparison to AB T cells?
Less variability than conventional TCR, together w/ CD3: | May play role in innate immune response
62
Where do GD T cells reside?
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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