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HIID > L11: T Cell Activation > Flashcards

L11: T Cell Activation Flashcards

1
Q

What are the phases of T cell responses?

A 
Antigen recognition
Activation
Clonal expansion
Differentiation
Effector functions
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2
Q

During the activation phase of T cell response, what causes proliferation or expansion?

A

Upregulation of IL-2 receptor on the T cells and upregulation of production of IL-2

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3
Q

CD3 molecules

A

T cell receptors are always non-covalently associated w/ CD3 molecules

There are different subunits of CD3, but all are non-covalently associated

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4
Q

ITAMs

A

Immunoreceptor tyrosine-based activation motif

This motif has signaling function

Is on the chains of CD3

Other receptors of the immune system also have one or more ITAMs associated

After there is antigen recognition, there isphosphorylation of ITAMs on the TCR as well as the CD3 molecule, which recruits another kinase to it

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5
Q

What is ZAP-70? (not what does it do)

A

Whole complex of ITAMs w/ kinase

This is one of the initial transcription factors involved after a T cell recognizes self-MHC and a foreign antigen

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6
Q

What are the 2(+1) competence signals for T cells?

A
  1. MHC+peptide
  2. Co-stimulation
  3. Cytokines
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7
Q

B7

A

Family of co-stimulators on an antigen present cell

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8
Q

CD28

A

Co-stimulator receptors on T cell

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9
Q

What causes initial phosphorylation of ITAMs? What results?

A

When TCR recognizes self-MHC and foreign peptide and CD28 recognizes a B7 molecule

This ultimately leads to production of IL-2 which leads to T cell proliferation and differentiation into effector cells; this is clonal expansion bc this one T cell is going to multiply many times

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10
Q

What does ZAP-70 do?

A

Phosphorylates LAT and SLP-76, initiating 4 downstream signaling molecules

Ultimately leads to activation and transcription of 3 important transcription factors: NFAT, NF-κB, and AP-1

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11
Q

What do NFAT, NFκB, and AP-1 do?

A

Bind to the promoter region of IL-2

Induce IL-2 gene so IL-2 is secreted; this happens very quickly since want proliferation to happen very quickly as well

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12
Q

What is difference in IL-2 receptor b/w naive and activated T cell?

A

Naive T cell: Part of IL-2 receptor is expressed (have the β and γ chains); have a moderate affinity for IL-2

Activated T cell: Once T cell recognizes foreign peptide, it becomes activated and expresses α chain (in addition to β, and γ chains); IL-2 receptor has high affinity for IL-2

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13
Q

IL-2

A

A cytokine that is a T cell growth factor

Is an autocrine bc it is produced by the T cell and has an effect on the T cell

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14
Q

What signals the T cell to enter the cell cycle?

A

Binding of IL-2 to its receptor

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15
Q

How much IL-2 is required to activate T cells?

A

100x more IL-2 required to activate naive vs. activated T cells

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16
Q

Activation of TH cell by what upregulates expression of IL-2?

A

Both signal 1 and costimulatory signal 2

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17
Q

What does upregulation of IL-2 and the IL-2 receptor lead to?

A

Proliferation

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18
Q

When does T cell division begin? How long is each cycle?

A

T cell division begins within 18 hours after activation

Each cycle takes about 6 hours

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19
Q

What leads to anergy?

A

Failure to deliver signal 2

Won’t have transcription of IL-2 and these cells will be anergic

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20
Q

What occurs in anergy?

A

Cells won’t actually die but will be circulating until normal death due to lifespan

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21
Q

What occurs when an anergic T cell encounters an APC that can deliver both signals?

A

The anergic T cell still cannot respond

Angergic T cell can’t be rescued

22
Q

What does requiring 2 signals for T cell activation do?

A

Reduces anti-self reactivity

Prevents unnecessary T cell activation since failure to co-stimulate leads to anergy

23
Q

What does co-stimulation lead to?

A

Upregulation of IL-2 production → 100-fold more IL-2 to activate the naive T cells →
increased transcription of IL-2 gene, increased stability of transcript, anti-apoptotic signals so that T cells survive

24
Q

Compare activation of naive vs. activated T cells

A

Naive: have a higher threshold of activation, primarily activated in lymphoid organs (primarily LN), primarily activated by DC, which delivers both MHC-AG and co-stimulation signals

25
Q

What is the best APC for naive T cell activation?

A

Dendritic cells

26
Q

Where does activation of activated T cells occur? Of naive T cells?

A

Naive: lymhoid organs (primarily lymph node)

Activated: at site of infection

27
Q

What gene expression occurs immediately following TCR ligation?

A

Immediate genes:
Expressed within half an hour

Transcription factors: c-Fos, c-Myc, c-Jun, NFAT, and NF-κB

These are immediately expressed so IL-2 is produced and T cells begin to expand

28
Q

What early genes are expressed following TCR ligation?

A

Early genes: 1-2 hours; IL-2, IL-2R, IL-3, IL-6, IFN-γ

29
Q

What late genes are expressed following TCR ligation?

A

Late genes: >2 days

Adhesion molecules (which will stabilize binding of the effector cell to the infected cell)

30
Q

Do the APCs constantly produce B7?

A

Dendritic cell: constitutive B7

Macrophage: inducible B7

B lymphocytes: inducible B7

31
Q

What leads to expression of APC?

A

CD40:CD40L co-stimulatory pair

32
Q

Where is CD40 expressed?

A

On APC

33
Q

Where is CD40L expressed?

A

On T cell

Is expressed following T cell recognition of antigen and self-MHC and CD28 to B7 signal

34
Q

What does CD40:CD40L cause?

A

Increased expression of B7, which enhances costimulation

T cells also secrete T cell-activating cytokines

35
Q

CTLA-4

A

A negative regulator of an immune response that is also expressed on the T cell

Has a higher affinity than CD28 for B7 and engages it in a multivalent orientation

36
Q

What has a higher affinity than CD28 for B7?

A

CTLA-4

37
Q

Describe formation of the immunological synapse

A

Before stimulation, the receptors are randomly assorted in the membrane → molecules on both the APC and T cell move together → the organized immunological synpase is formed; consists of the central and peripheral supramolecular activating complex (cSMAC and pSMAC)

Helpful bc all of the cytokine secretion will occur within this synapse

38
Q

Calcineurin

A

Critical for activation of NFAT

39
Q

Cyclosporin

A

Very potent immunomodulatory drug

Used commonly for transplantation and treatment of immune disorders

Acts on calcineurin and thus inhibits NFAT and downregulates immune response

40
Q

FK506

A

Very potent immunomodulatory drug

Used commonly for transplantation and treatment of immune disorders

Acts on calcineurin and thus inhibits NFAT and downregulates immune response

41
Q

ZAP-70 tyrosine kinase deficiency

A

Leads to a type of SCID (severe combined immunodeficiency disease)

42
Q

Bruton’s (X-linked) agammaglobulinemia

A

Caused by a defect in Btk

43
Q

X-linked hyper-IgM

A

Caused by mutation in CD40L on T cells

44
Q

What is an example of how cytokines transduce signals?

A

Through JAK/STAT pathway

45
Q

What does cytokine signaling result in?

A

Results in induction of genes with appropriate response elements

46
Q

What does a cytokine being pleiotropic and redundant mean?

A

Pleiotropic: can act on many different cell types
Redundant: certain cytokines have similar functions

47
Q

What can deficiency in cytokine signaling lead to?

A

Immunodeficiency

48
Q

What kind of cytokine receptor families are there?

A

Homodimeric receptors

Heterodimeric receptors w/ a common chain

Heterodimeric receptors (no common chain)

TNF receptor family

Chemokine receptor family

49
Q

Describe signaling through cytokine receptors?

A

Cytokine receptors consist of at least 2 chains, the cytoplasmic domains of which bind Janus kinases (JAKs) → cytokine binding dimerizes the receptor, bringing together the cytoplasmic JAKs, which activate each other and phosphorylate the receptor → Transcription factors (STATs) binds to the phosphorylated receptors and are in turn phosphorylated by the activated JAKs → phosphorylated STATs form dimers that translocate into the nucleus to initiitate new gene transcription

50
Q

How does the interferon (IFN) family of cytokines signal?

A

There are different receptors for Type I, II, and III IFNs, but all involve JAK/STAT

Also involves a series of different transcription factors called interferon response factors (IRFs) that bind to interferon response elements (ISREs) in promoter regions of certain genes

51
Q

What is IL-2R gamma chain shared by?

A

IL-2, -4, -7, -9, -11, and -15R

52
Q

What does lack of IL-2R gamma chain cause?

A

Defective signaling through IL-2Rs

Since IL-7 is also needed for lymphocyte development, this deficiency therefore results in X-linked SCID

HIID (27 decks)

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