Lecture 13, Cell Basis of Tolerance Flashcards Preview

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Flashcards in Lecture 13, Cell Basis of Tolerance Deck (45):
1

What is another term for negative selection?

Clonal deletion

2

What are the 3 methods/cells of peripheral tolerance?

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

3

What do Myeloid Derived Suppressor Cells (MDSCs) do?
What cytokine tends to activate them?

- 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

4

Describe the process of clonal anergy.

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

5

What is the very general function of Tregs?

Suppress immune response

6

What is the AIRE transcription factor responsible for?

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

7

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

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

8

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

Peripheral tolerance

9

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

NO and arginase

10

Name the 3 types of Tregs.

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

11

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

- Thymus
- FOXP3+
- IL-2

12

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

- 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

13

Recall: what are Hassall's corpuscles?
*What occurs there?

Groups of epithelial cells within the thymic medulla.
- Site for generation of Tregs

14

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

Thymic stromal lymphopoietin (TSLP)

15

Recall: Mutations in the FOXP3 gene causes what dz?

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

16

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

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

17

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?

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

18

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

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

19

What 2 vitamins act as cofactors do induce iTregs?

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

20

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

- FOXP3-
- IL-10
- Immunosuppression and maintenance of tolerance

21

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

Vitamin D

22

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

TGF-beta and IL-27

23

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

IL-10 and TGF-beta
(soluble factors)

24

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

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

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

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

26

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

Silencing process (degradation of signaling molecules)

27

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

- 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

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

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

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

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

Gene: AIRE: Phenotype of mutant or knockout mouse?

Destruction of endocrine organs by ABs, lymphocytes

31

Gene: AIRE: Mechanism of failure of tolerance?

Failure of central tolerance

32

Gene: AIRE: Human disease?

Autoimmune potyendocrine syndrome (APS)

33

Gene: FoxP3: Phenotype of mutant or knockout mouse?

Multi-organ lymphocytic infiltrates, wasting

34

Gene: FoxP3: Mechanism of failure of tolerance?

Deficiency of regulatory T cells

35

Gene: FoxP3: Human disease?

IPEX

36

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

Inflammatory bowel disease: antierythrocyte and anti-DNA
auto-ABs

37

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

Defective development, survival or function of regulatory T cells

38

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

None known

39

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

Lymphoproliferation; T cell infiltrates in multiple organs

40

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

Failure of anergy in CD4+ T cells

41

Gene: CTLA-4: Human disease?

CTLA-4 polymorphisms associated with several
autoimmune diseases

42

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

Inflammatory bowel disease

43

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

Failure of T cell and accessory cell suppression against commensal bacterium

44

Gene: IL-10: Human disease?

Polymorphism link to IBD, various cancers

45

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

Self
Foreign