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Immunology I > T-cells > Flashcards

T-cells Flashcards

1
Q

N: Differentiation of T helper cell subsets is regulated by polarizing cytokines.
Name the Polarizing cytokines, Master transcriptional regulators, Effector cytokines and Effector functions in case differentiation into:

T_FH cells

A

Polarizing cytokines: IL-6, IL-21
Master transcriptional regulator: Bcl-6
Effector cytokines: IL-4, IL-21
Effector Function: B cell help in germinal centers

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2
Q

N: Differentiation of T helper cell subsets is regulated by polarizing cytokines.
Name the Polarizing cytokines, Master transcriptional regulators, Effector cytokines and Effector functions in case differentiation into:

T_H1 cells

A

Polarizing cytokines: IL-12, IL-18, IFN-ɣ
Master transcriptional regulator: T-Bet
Effector cytokines: IFN-ɣ, TNFa
Effector Function: cell-mediated immunity, macrophage activation, inflammation

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3
Q

N: Differentiation of T helper cell subsets is regulated by polarizing cytokines.
Name the Polarizing cytokines, Master transcriptional regulators, Effector cytokines and Effector functions in case differentiation into:

T_H2 cells

A

Polarizing cytokines: IL-4
Master transcriptional regulator: GATA3
Effector cytokines: IL-4, IL-5, IL-13
Effector Function: allergic and anti-helminth responses

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4
Q

N: Differentiation of T helper cell subsets is regulated by polarizing cytokines.
Name the Polarizing cytokines, Master transcriptional regulators, Effector cytokines and Effector functions in case differentiation into:

T_H17 cells

A

Polarizing cytokines: IL-1, IL-6, IL-23, TGF-β
Master transcriptional regulator: RORɣt
Effector cytokines: IL-17A, IL-17F, IL-22
Effector Function: inflammation

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5
Q

N: Differentiation of T helper cell subsets is regulated by polarizing cytokines.
Name the Polarizing cytokines, Master transcriptional regulators, Effector cytokines and Effector functions in case differentiation into:

induced T_Reg cells

A

Polarizing cytokines: IL-2, TGF-β
Master transcriptional regulator: FOXP3
Effector cytokines: IL-10, TGF-β
Effector Function: Regulation, supression of immune and inflammatory responses

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6
Q

Ž - What is the difference between central and peripheral tolerance?

A

central: positive and negative selection of lymphocytes in primary lymphoid organs

peripheral: inducing immune responce or anergy in secondary lymphoid organs and tissues
- if T cell recognizes Ag without the presence of costimulatory signal, it becomes tolerant (anergy)
- if costimulatory: gets primed, activated and can THEN recognize Ag in absence of costimulatory signal, but respond to it

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7
Q

Ž - Describe the immunological synapse that forms between T cell and APC. Which two complexes are formed?

A

SMAC = supramolecular activating complex

cSMAC forms in the centre = TCR:MHC(p) and coreceptors

pSMAC around cSMAC = adhesion molecules:ligands

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8
Q

Ž - Which cytokine is produced and forms a positive feedback loop upon T cell activation via signal 1 and 2?

A

IL-2

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9
Q

Ž - Why are CD8 positive T cells stimulated with a bit of delay?

A

APCs get help from CD4+ T cells to upregulate additional costimulatory molecules like CD40 and 4-IBBL

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10
Q

Ž - What is the difference between natural and induced Tregs?

A

both CD4+, Foxp3

natural: acquire regulatory fate while still in thymus
induced: become differentiated in the periphery

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11
Q

Ž - Via which signaling pathway does the CD4 T cell differentiation into different types happen?

A

JAK/STAT

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12
Q

Ž - TCR - What is the main “job” of TCR?

A

recognizes peptide Ag in context of MHC
subsequently, that means that it’s supposed to control pathogen infection while avoiding tissue damage (tolerance against self-Ag, even in the presence of inflammation)

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13
Q

Ž - TCR - Describe Miller’s thymectomy experiments.

A

thymectomy = removing thymus

thymectomy at neonatal stage: leads to infections, much fewer lymphocytes in circulation and tissues, mice incapable of rejecting tissues

thymectomy in adults: no direct effects, but if you do full body irradiation, immune system is unable to reconstitute (it is thymus dependent)

In combinations with transplants:

  • strain A does not accept strain B’s skin graft
  • strain A does accept strain B’s skin graft upon thymectomy
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14
Q

Ž - TCR - Describe TCR structure (whole complex, but without coreceptors).

A

TCR itself: alpha and beta chain (has no signaling subunits)
+ 2 x CD3 (delta-epsilon; epsilon-gamma): signaling subunits
+ zeta homodimer: signaling subunits too

each CD3 component = 1 ITAM
each zeta = 3 ITAMs

held in close proximity by electrostatic interactions

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15
Q

Ž - TCR - TCR receptors undergo gene rearrangement. Describe how it happens and which sequences are important.

A

VDJ recombination (V, D and J segments present in beta chain, only VJ in alpha; different distribution of genes for alpha and beta chain)

V/D/J gene = recombination substrate is flanked by conserved ‘recombination signal sequences’ aka RSS

RSS get recognized by VDJ-recombinase because they contain 2 consensus sequences:
1 heptamer in each sequence
1 A/T rich nonamer in each sequence
separated by non-conserved 12 or 23 nt spacer

these spacers are facing each other in the sequence:
7-23-9 vs 9-12-7

RSS recognizes them, brings nonamers together
hairpin loop forms
DNA is nicked
break has to be repaired (based on template DNA = P-nucleotides),
but while doing that, random nucleotides get inserted which generate diversity (N-nucleotides, added by terminal deoxynucleotide transferase TdT)

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16
Q

Ž - TCR - How do we reach high TCR diversity compared to BCR? Compare.

A

V(D)J recombination in both,
but TCRalpha has more J-regions than BCR light chain,
which creates more diversity

TCR has no somatic hypermutations tho,
so there is no changes in CDRs 1 and 2 like in BCRs (remain germline encoded)
(DJ recombination in TCR causes CDR3 diversity)

+ CDR3 as MHC:p contact is highly variable (induced fit model of binding)

17
Q

Ž - TCR - Which molecules are TCRs coreceptors and what do they contact? Are their sequences variable?

A

CD4 and CD8
contact invariant regions of respective MHCs

invariable

18
Q

Ž - TCR - Name several different T cell accessory molecules that assist in T cell (not necessarily TCR) signal transduction.

A 
CD4/8 : MHCII/I
CD28 : CD80/86
CTLA-4 : CD80/86
LFA-2 : LFA-3 (not the same thing as LFA-1 for homing)
CD45R : CD22 (on B cells)
19
Q

Ž - TCR - Describe TCR signaling.

A

TCR:CD3 complex recognizes MHC:p on APC (+ coreceptor CD4/8 interaction with MHCs)
this leads to phosphorylation of both Tyr in ITAMs of the T cell receptor (primarily by Lck which is constitutively associated with CD4/8 IC domains and kept inactive by phosphorylation; also Fyn)

P-ITAMs (SH2 domains) recruit and activate ZAP-70
ZAP-70 phosphorylates scaffold proteins and promotes PI3K activation (PIP2 -> PIP3)
multiple binding sites on these scaffold proteins recruit several additional adaptor and enzymes that initiate 4 essential downstream signaling modules

1) Akt -> increased cellular metabolic activity
2) PLC-gamma -> DAG and IP3 -> Ca entry, Ras activation, PLC-theta -> TF activation (NFAT, AP-1, NFkB respectively)
3) Vav -> actin polymerization and cytoskeletal rearrangement
4) ADAP -> enhanced integrin adhesiveness, clustering

20
Q

Ž - What are immune checkpoints (list examples) and where are they used in therapy?

A

immune checkpoints normally mediate immune tolerance to stop collateral tissue damage = negatively regulate immune response to stop T cell proliferation

e. g. CTLA-4:
- binds B7 more avidly than CD28 and delivers inhibitory signals to activated T cells
- distinct binding orientation allows clustering

e. g. PD-1:
- binds B7-family member ligand PD-L1

therapy: melanoma treatment to increase antitumor response (side effect = autoimmunity)

21
Q

Ž - Which organ is a dedicated differentiated niche for T cells? Describe its location and anatomy.

A

thymus
above heart
2 areas: cortex and medulla

in cortex: cTECs (thymus epithelial cells), thymocytes, macrophages
in medulla: mTECs, DCs, macrophages

22
Q

Ž - What is genetic model for neonatal thymectomy?

A

Foxn1 mutant mouse

athymic, but also nude

23
Q

Ž - Which master TF specifies development of T lymphocytes from common lymphoid progenitor?

A

Notch

24
Q

Ž - Which FACS sorting is used to separate thymic progenitors as they pass through differentiation stages?
Which FACS sorting is used to separate double negative thymic progenitos as they pass through differentiation stages?
In which order do they pass?
What do you see if you sort T cells from Notch KO mice?

A

CD4 vs CD8: from DN to DP, then either CD4+ or CD8+
CD25 vs CD44: from left upper quadrant to right upper, then righ lower, finish in left lower

Notch KO: no cells past DN1 stage

25
Q

Ž - Where in thymus are Notch ligands expressed?

A

on cTECs

26
Q

Ž - TCR - Explain somatic rearranging of TCR genes and describe what is expressed on the surface of the cell.

A
  1. maturing DN thymocyte is specified for T cell differentiation by Notch signaling
  2. beta-chain DJ rearrangement, followed by VDJ (= beta selection)
  3. beta chain is expressed in cytoplasm = commitment step
  4. beta chain associates with pTalpha to form pre-TCR - if successful, beta rearrangement stops, cell proliferates
  5. alpha rearrangement starts and TCR is expressed on the surface of DP thymocyte
27
Q

Ž - TCR - What is the connection between pre-TCR expression and allelic exclusion?

A

once pre-TCR is expressed on the cell surface, Rag genes are transiently shut down to prevent rearrangement of the genes on the second TCR beta locus

28
Q

Ž - How many thymocytes are developed per day?

A

5 x 10^7

29
Q

Ž - In T cell development, which selections happen and in which order?

A
  1. positive (does TCR recognize self-restricted MHC)

2. negative (does it recognize self antigens)

Immunology I (8 decks)

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