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HD Exam 1 > Lecture 13, Cell Basis of Tolerance > Flashcards

Lecture 13, Cell Basis of Tolerance Flashcards

1
Q

What is another term for negative selection?

A

Clonal deletion

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2
Q

What are the 3 methods/cells of peripheral tolerance?

A
  1. Regulatory T cells
  2. Myeloid Derived Suppressor Cells (MDSCs)
  3. Clonal Anergy (T cells)
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3
Q

What do Myeloid Derived Suppressor Cells (MDSCs) do?

What cytokine tends to activate them?

A
  • APCs that can block T cell responses (while MDSC is presenting Ag to the T cell)
    “To protect the host from the harmful effects of excessive immune stimulation during acute and chronic infections, and to limit the generation of autoimmune responses towards tissue antigens released by trauma”
  • e.g. IFN-γ
  • Often tumor-associated
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4
Q

Describe the process of clonal anergy.

A
  • When T cells are stimulated in a manner that are not “complete,” cells become non-responsive to further stimulation.
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5
Q

What is the very general function of Tregs?

A

Suppress immune response

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6
Q

What is the AIRE transcription factor responsible for?

A
  • Gives APCs self-antigen from non-thymic parts of the body to present to developing thymocytes for negative selection in the thymic medulla.
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7
Q

Loss of function of AIRE genes could lead to what disease?

A

Autoimmune Polyendocrine Syndrome (APS)

- Endocrine organs are destroyed by ABs and lymphocytes. (failure of central tolerance)

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8
Q

After central tolerance is complete, what other process do T cells continually undergo to make sure the do not react to self?

A

Peripheral tolerance

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9
Q

In response to IFN-gamma, what do MDSCs produce that effectively suppresses T cell activation?

A

NO and arginase

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10
Q

Name the 3 types of Tregs.

A
  1. nTregs (Natural)
  2. iTregs (Inducable)
  3. Tr1 cells
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11
Q

Where are nTregs generated?
Are they FOXP3 + or - ?
What cytokine is essential for their maintenance?

A
  • Thymus
  • FOXP3+
  • IL-2
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12
Q

From what cells do nTregs come from?
How does their background serve their function?
Where in the thymus does this take place?

A
  • A group of thymocytes that have reactivity against *self-ag’s are converted into nTregs.
  • These are self-reactive clones, but they don’t attack, don’t acquire effector functions to promote immune responses. Instead, activated by self ag to acquired selective activity.
  • Hassalls corpuscles
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13
Q

Recall: what are Hassall’s corpuscles?

*What occurs there?

A

Groups of epithelial cells within the thymic medulla.

- Site for generation of Tregs

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14
Q

What molecule do Hassall’s corpuscles give off that helps w/the differentiation of FOXP3+ Tregs?

A

Thymic stromal lymphopoietin (TSLP)

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15
Q

Recall: Mutations in the FOXP3 gene causes what dz?

A

Immunodysregulation, Polyendocrinopathy, and Enteropathy, X-linked (IPEX)
- Suffer from multiple tissue damages caused by self-reactive T cells (due to lack of Tregs)

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16
Q

What factors can induce iTregs?
Are they FOXP3 + or - ?
What 2 cytokines are critical for their maintenance?

A
  • Environment (food), commensal organisms, pathogens and tumors
  • FOXP3+
  • TGF-beta and IL-2
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17
Q

What cytokine is critical for the induction of both Th17 cells and iTregs?
What other cytokine will decide whether the helper T cell will become an iTreg vs a Th17 cell?

A
  • TGF-beta

- IL-6 (IL-6+ will create Th17, IL-6- will created iTreg)

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18
Q

Generally, how do Th17 cells differ in function from iTregs?

A

Th17 cells are the opposite of iTregs.

  • Th17 cells are the most potent pro-inflammatory T cells.
  • Th17 cells also require TGF-beta, but requires pro-inflammatory IL-6, often produced by activated macrophages
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19
Q

What 2 vitamins act as cofactors do induce iTregs?

A

Vitamin A (retinoic acid, RA) and/or D

20
Q

Are Tr1 cells FOXP3 + or - ?
*What is the major cytokine they release?
What is their overall function?

A
  • FOXP3-
  • IL-10
  • Immunosuppression and maintenance of tolerance
21
Q

What vitamin is linked to the generation of Tr1 cells (by upregulating IL-10)?

A

Vitamin D

22
Q

Tr1 cells develop in response to antigenic stimulation when what 2 cytokines are present in the environment?

A

TGF-beta and IL-27

23
Q

While Tr1 cells mainly use IL-10 to enhance their functions, FOXP3+ Tregs use what 2 cytokines?

A

IL-10 and TGF-beta

soluble factors

24
Q

What signaling receptor/ligand combo is absent when clonal anergy occurs w/T cells?

A

Anergy is induced when antigen is presented (TCR + MHC) in the absence of co-stimulatory signal (CD28, on T cell).
- Ligand of CD28 are B7.1 (CD80) and B7.2 (CD86)

25
Q

How come CD28 on T cells binding B7 limits the risk of false stimulation?

A

B7 is only present on professional APCs, thus limiting what can stimulate a T cell.

26
Q

What’s the name of the process that occurs if a T cell cannot bind B7 on its APC target cell in the thymus?

A

Silencing process (degradation of signaling molecules)

27
Q

What cells produce CTLA-4?
What receptor does CTLA-4 bind?
How does CTLA-4 function?
What does it recruit?

A
  • Tregs
  • B7
  • Competes w/CD28 of T cell for binding at B7 (has higher affinity than CD28, so it will win out)
  • Also recruits signaling molecules that suppress TCR signaling and blocks ag-activation.

(critical role in immune homeostasis)

28
Q

How could you take advantage of CTLA-4 to treat autoimmune diseases such as Graft-Versus-Host Disease and psoriasis?

A

Man-made CTLA4-IG can be given exogenously to mimic CTLA4, thus inhibiting the T cell activation and improving symptoms of GVH and psoriasis.

29
Q

How could CTLA-4 be taken advantage of in “Immune Checkpoint Blockade”?
What major disease category would be good to treat this way?

A

Many costimulatory molecules (e.g. CTLA4) work in an inhibitory manner to T cells. For cancer immunotherapy, blocking these inhibitory molecules provoked robust anticancer immune responses (increased T cell stimulation)
- Novel cancer tx

30
Q

Gene: AIRE: Phenotype of mutant or knockout mouse?

A

Destruction of endocrine organs by ABs, lymphocytes

31
Q

Gene: AIRE: Mechanism of failure of tolerance?

A

Failure of central tolerance

32
Q

Gene: AIRE: Human disease?

A

Autoimmune potyendocrine syndrome (APS)

33
Q

Gene: FoxP3: Phenotype of mutant or knockout mouse?

A

Multi-organ lymphocytic infiltrates, wasting

34
Q

Gene: FoxP3: Mechanism of failure of tolerance?

A

Deficiency of regulatory T cells

35
Q

Gene: FoxP3: Human disease?

A

IPEX

36
Q

Gene: 1L-2: IL-2R: Phenotype of mutant or KO mouse?

A

Inflammatory bowel disease: antierythrocyte and anti-DNA

auto-ABs

37
Q

Gene: 1L-2: IL-2R: Mechanism of failure of tolerance?

A

Defective development, survival or function of regulatory T cells

38
Q

Gene: 1L-2: IL-2R: Human disease?

A

None known

39
Q

Gene: CTLA-4: Phenotype of mutant or knockout mouse?

A

Lymphoproliferation; T cell infiltrates in multiple organs

40
Q

Gene: CTLA-4: Mechanism of failure of tolerance?

A

Failure of anergy in CD4+ T cells

41
Q

Gene: CTLA-4: Human disease?

A

CTLA-4 polymorphisms associated with several

autoimmune diseases

42
Q

Gene: IL-10: Phenotype of mutant or knockout mouse?

A

Inflammatory bowel disease

43
Q

Gene: IL-10: Mechanism of failure of tolerance?

A

Failure of T cell and accessory cell suppression against commensal bacterium

44
Q

Gene: IL-10: Human disease?

A

Polymorphism link to IBD, various cancers

45
Q

nTegs mainly protect against _______ Ag, while iTregs mainly protect against _______ Ag.

A

Self

Foreign

HD Exam 1 (15 decks)

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