Cellular Basis for Immunological Tolerance

Question 1

Define immunological tolerance and give some examples

Answer 1

Non-responsiveness to specific Ag

Tolerance to self-Ag, food particles, commensal bacteria, pregnancy

Question 2

What is an example of a hyper-immune disorder?

Answer 2

Allergy

Question 3

What is an example of an autoimmune disease?

Answer 3

IBD

Question 4

How do tumors hijack the immune system?

Answer 4

They create an environment that the immune system recognizes as self, and is thus tolerant to it

Question 5

What is central tolerance?

Answer 5

elimination of T cells that are reactive to Ag presented in the thymus - self Ag

Question 6

What are three mechanisms of peripheral tolerance?

Answer 6

Tregs

Myeloid Derived Suppressor Cells (MDSC)

Inappropriate or insufficient co-stimulation of a T cell in presence of its Ag

Question 7

How are Tregs involved in peripheral tolerance?

Answer 7

Tregs are professional T cells that are designed to impose suppression to other T cells and accessory cells

Question 8

How are MDSCs involved in peripheral tolerance?

Answer 8

A group of myeloid cells become potent immunoregulatory cells when exposed to pro-inflammatory cytokines such as IFN-gamma and will kill activated T cells to prevent further proliferation

Question 9

Define anergy and explain how it is involved in peripheral tolerance

Answer 9

When a T cell is inappropriately or insufficiently co-stimulated in the presence of its Ag, the will become anergic, or, non-responsive to further stimulation

Question 10

What does intrathymic clonal deletion do?

Answer 10

deletes cells that are autoreactive (have high affinity to Ag present in the thymus)

Question 11

How is AIRE involved in central tolerance?

Answer 11

It produces tissue specific self Ag that can be presented to developing thymocytes

Question 12

What do cells that have an intermediate affinity to self become?

Answer 12

they are not eliminated by negative selection, but rather mature into Foxp3+ Tregs

Question 13

Where are Tregs generated?

Answer 13

Hassall’s corpuscle

Question 14

What does loss of AIRE result in?

Answer 14

Autoimmune Polyendocrine Syndrome (ARS) - endocrine organs are destroyed by Ab and lymphocytes

Question 15

What are MDSCs?

Answer 15

Cells of lymphoid origin that can suppress T cell responses

Question 16

To what do MDSCs respond?

Answer 16

pre-existing inflammations, activated by pro-inflammatory cytokines such as IFN-gamma (produced by Th1 and CD8+ - found in inflammatory states)

Question 17

How do MDSCs suppress T cell response?

Answer 17

Release NO and arginase (will deprive the cell of arginine)

Question 18

what are nTregs?

Answer 18

cells generated in the thymus that suppress other immune cells, mainly T cells

Question 19

What is important about the fact that nTregs are generated in the thymus?

Answer 19

their Ag diversity is mainly limited to self Ag

Question 20

what are iTregs?

Answer 20

These Tregs can be manipulated by the environment, commensal bacteria, pathogen, tumors

Question 21

What induces iTregs and what cytokines play a role?

Answer 21

iTregs are induced by APCs in the mucosa, and require Vit A and D. IL-2, TGF-beta are involved in iTreg stimulation.

IL-6 is inhibitory

Question 22

What are Tr1 cells?

Answer 22

TGF-beta and IL-27 induces these cells, which are NOT Foxp3+

produce IL-10

Question 23

What will result from the failure of peripheral tolerance?

Answer 23

IPEX (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked):

caused by loss or dysfunction of foxp3, leads to systemic autoimmunity

Question 24

What is clonal Anergy?

Answer 24

the state of T cells when they are not responsive to Ag

Question 25

When does clonal anergy occur?

Answer 25

When T cells are presented Ag in the absence of co-stimulation via CD28

Question 26

Who expresses the ligand for CD28? (and what is it?)

Answer 26

The ligand for CD28 is CD80/86 and is expressed by a select group of APCs

Question 27

What is CTLA-4?

Answer 27

CTLA-4 is expressed by T cells after activation and competes with CD28 for B7 binding - CTLA-4 has higher affinity for B7, and will thus bind preferentially over CD28

CTLA-4 also recruits signaling molecules that suppress T cells and blocks Ag activation

Question 28

how can we use CTLA-4 in BMT and autoimmune diseases?

Answer 28

give CTLA-4Ig which can block T cell activation from the outside