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Immunology week 7 > iNKT and MAIT cells > Flashcards

iNKT and MAIT cells Flashcards

1
Q

Whats the difference between NK and iNKT cells in terms of the TCR?

A

NK cells have NO TCR.

iNKT cells have a rearranged TCR!

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2
Q

What is different about iNKT TCR versus conventional T cells?

A

It has a (semi) invariant TCR! iNKT cells have the same invariant Va24 a chain in humans. This is almost exclusively coupled to a common VB11 B chain.
So iNKT cells invariant TCR is: Va24/ VB11.

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3
Q

Whats the mouse semi invairatn iNKT cell TCR?

A

Va14/ VB2/7/8.

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4
Q

Similarlity of iNKT cells to CD1 group 1 restricted TCRs?

A

iNKT can be considered a subset of CD1 restricted cells. BUT iNKT cells have an invariant Va24/B11 TCR which is restricted to the monomorphic CD1d.

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5
Q

what does Va24/Ja18 mean?

A

It means that the variant portion of TCR a chain has the identical CDR3 (Ja18).

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6
Q

Are iNKT cells abundant?

A

YES in the liver they account for 10-20 percent of the lymphocytes. IN spleen it is 1-2%.

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7
Q

What is the strongest agonis for iNKT cells? Can CD1d and iNKT cells recognise self antigens?

A

a-galactosylceramide GalCer. A lipid obviously, but in an anomeric configuration.
Can recognise self lipid B-GlcCer but in B anomeric configuration, and binds with lower affinity.

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8
Q

Where was GalCer orignigally found? And name another lipid that iNKT cells recognise

A

a-GalCer orignially found in symbitoic bacteria of sponges.

Another bacterial lipid recognised is a-GalDAG.

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9
Q

What co receptors do iNKT mostly have?

A

Most double negative and some CD4+, very few CD*8+.

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10
Q

What is the semi invariant TCR for MAIT cells?

A

Va7.2 (Ja33) which binds to a limited repertoire of VB chains (VB6 and VB20).

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11
Q

What marker is shared between NK cells, iNKT cells and MAIT cells?

A

It is the CD161.

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12
Q

What co receptors do MAIT cells mostly express?

A

The majority are CD8+ and some are DN, very few are CD4+.

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13
Q

What are the antigens for MAIT cells and what MHC like molecule are they presented on?

A

Presented on MR1 moelcules, raboflavin derivatieves (involved in the synthesis of vitamin B2) which is done by foreign microbes.

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14
Q

What molecule do MR1 and CD1 both bind to for antigen presentation?

A

B2 microglobulin!.

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15
Q

What is the inhibitory derivative that binds with low affinity to MR1?

A

It is derived from the folate (vitamin B9) pathway.

6-FP.

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16
Q

Why is 6-FP only inhibitory?

A

Because it only forms the schiff base (k43), does not have ribityl tail that 5-OP-RU binds.

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17
Q

How is 5-Op-RU bound to MR1 and why is it unstable?

A

Binds with high affinity because it engages the schiff base and forms covalent bonds with ribityl tail.

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18
Q

What kind of bacteria express riboflavin derivatives?

A

Many commensal bacteria form these antigens and some yeasts.

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19
Q

Why may there be possible other antigens?

A

Because riboflavin derivatives only bind the a pocket of MR1, leave space of another M pocket.

20
Q

How are MR1 molecules only expressed at the correct time?

A

Because they are stored intracellularly in the ER in conformation receptive to the ligand. Riboflavin binding will neutralise the K43 positive charge, changing MR1 conformation for its surface expression.

21
Q

What do vitamin B2 derivatives NOT use to transport across ER?

A

Unkonw what they do use, but DO NOT use TAP.

22
Q

why is expression of MR1 limited?

A

Becuase they are abundant cells (40% of liver lymphocytes), and many commensal bacteria produce MR1 antigens. Expression on surface and activation of MAIT cells only wanted during infection.

23
Q

How can you study iNKT cells (toolbox) with FACs?

A

You can use anti Va24 antiboides and anti CD161 ab. Also use CD1d antigen loaded tetramers.

24
Q

How to study MAIT cells with FACs?

A

Using anti-Va7.2 Ab and anti CD161 Ab as well as MR1 loaded tetramers (6-FP as a control for tetramers).

25
Q

Can human MAIT and iNKT invairant TCRs bind mice CD1d and MR1?

A

Yes, these systems are highly conserved.

26
Q

Where do both iNKT and MAIT cells develop? What cells are important for their selection?

A

In the thymus, both are selected by DP thymocytes expressing CD1d and MR1. Commensal antignes for MR1 thought to be important for MAIT cell selection and expansion.
iNKT CD1d endogenous antigen unknown.

27
Q

What TF is important for differentiation of both MAIT and iNKT cell subsets?

A

The TF PLZF is important.

28
Q

How does PLZF levels drive iNKT cell differentiation?

A

PLZF very low, EBP4+, IL10+ iNKT cells,
PLZF low: iNKT1 IFN-y producing (and IL-4+) T-bet
PLZF int: IL-17 RORyt iNKT17
PLZF high: iNKT2 IL-4 GATA3

29
Q

What two subsets are there for MAIT cells?

A

MAIT T-bet

MAIT RORyt

30
Q

What evidence is there that MAIT and NKT cells are important in viral infections? How might they be activated?

A

NKT- and MR1- deficient mice were more susceptible to influenza infection.
Addition of MAIT cells to MR1- mice improved survival in infection.
Suggests MAIT cells can be protective in viral responses independent of MR1. e.g. cytokines?

31
Q

What evidence is there that MAIT and NKT cells are protective in autoimmunity?

A

NKT- and MR1- deficient NOD mice developed diabetes faster than WT.

32
Q

Evidence that NKT cells may have roles in immunosurveillance of tumour cells?

A

NKT- mice had higher incidence of tumour formation.

33
Q

What did the incidence of tumour formation in MR1- show?

A

That MR1- deficient mice were more tumour free- MR1 may have promote tumours (independently of MAIT cells?)

34
Q

Evidence that NKT cells may have roles in immunosurveillance of tumour cells?

A

NKT- mice had a higher incidence of tumour formation.

35
Q

What did the incidence of tumour formation in MR1- show?

A

That MR1- deficient mice were more tumour free- MR1 may have promoted tumours (independently of MAIT cells?)

36
Q

What cells can MAIT/ iNKT cells interact with to bridge innate and adaptive immunitY?

A

Can interact with adaptive cells like B cells (if presenting CD1d/MR1 with the antigen that can stimulate Antibody production).

With MDSCs.

DCs, license DCs, DC producitno of IL-12 can help iNKT cells stimulate NK cells

DCs interact with CD4 and CD8 cells.

37
Q

What peripheral maturation is required in MAIT cells?

A

Requires microflora for expansion of effectors/memory. This is dependent on riboflavin derivatives of commensal bacteria, as key enzymes knocked out prevent expansion.

38
Q

In what way can these innate-like T cells be triggered independently of TCR?

A

Via cytokines.

39
Q

Which cell type MAIT or iNKT can be activated by APC cytokines in viral infections like dengue?

A

MAIT cells..

40
Q

Indirect pathway of iNKT cell activation?

A

through cytokines from DCs and endogenous lipid on CD1d?

41
Q

What disease may MAIT cells be protective and suppressive?

A

In type 1 diabetes! MR1- deficient mice had a lower incidence of diabetes. But MAIT cells can help to destroy islet cells!

42
Q

In H.pylori infection and SLE mouse model, MR1- deficient mice had better atrophy score and increased survival. What does this mean for MAIT cells?

A

That in this context, MAIT cells may be pathogenic in this infection in gut and in SLE.

43
Q

Theory that MAIT cells may have repair potential during homeostasis?

MR1- deficient mice had slower re epitheliasaiot during wound repair.

A

Low level riboflavin derivatives from commensal bacteria may cuase their expansion and production of repair cytokines e.g. IL17 and TGFa, IL-22 during homeostasis.
In an inflammatory environment they may switch to producing inflammatory cytokines and cytotoxic granules.

44
Q

why are monogenic systems attractive for therapies?

A

Don’t have to worry about polymorphic HLA genes, but still have an inbuilt system of specificity. Can develop an off the shelf therapy.

45
Q

Whilst MR1- deficinet mice did have better outcome (suggests lack of MAIT is positive for tumours). Evidence against this?

A

Some T cells have been isolated that don’t have the MAIT TCR, but have TCR that recognises Tumour antigens from a variety of tumours via MR1.

Immunology week 7 (4 decks)

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