Cellular Basis for Immunological Tolerance

Question 1

What does “immunological tolerance” mean?

Answer 1

The immune system does not respond to a specific antigen.

Question 2

What are some well-known targets for tolerance?

Answer 2

• antigens from self-tissues

- non-self antigens that we don’t want to attack, like food, commensal bacteria, and fetuses

Question 3

What are the clinical implications of a loss of tolerance to self-antigens?

Answer 3

autoimmune diseases/disorders

Question 4

What does central tolerance refer to?

Answer 4

elimination of T and B-cell clones that are reactive to self-antigens

Question 5

What is the function of the AIRE gene?

Answer 5

It enables thymic stromal cells to express non-thymic genes and present self-antigens to developing thymocytes, enabling the immune system to remove cells that are reactive against antigens present in non-thymic tissues

Question 6

What are Myeloid Derived Suppressor Cells (MDSCs)?

Answer 6

cells that produce several molecules that inhibit activated T-cells to expand and prevent further expansion; activated by IFN-gamma

Question 7

Refers to a state of T-cells in which they are unresponsive to antigen stimulation.

Answer 7

clonal anergy; happens when T-cells are presented antigens in the absence of a crucial co-stimulator

Question 8

What is the significant difference b/t tTregs and pTregs?

Answer 8

• tTregs mature in the thymus and are mostly self-reactive
• pTregs are generated after thmyocytes migrate out of the thymus, and they can be reactive to foreign materials (commensal bacteria, cancer)

Question 9

What does IPEX stand for?

Answer 9

Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked

Question 10

What is IPEX caused by?

Answer 10

the loss or dysfunction of the FOXp3 transcription factor

Question 11

When to T-cells become anergic and unable to respond to further stimulation?

Answer 11

When the antigen is presented by APCs that do NOT express CD80/CD86 that binds with CD28 (ex: tumor cells).

Question 12

What does CTLA-4 do?

Answer 12

It competes with CD28 for the CD80/CD86 binding site and will ultimately win because it has a higher affinity. This blocks T-cell activation. CTLA-4 also recruits signaling molecules that suppress TCR signaling and further block activation.

Question 13

Which cells constantly express CTLA-4?

Answer 13

Tregs!

Question 14

True or false: Tregs require direct cell-cell contact for their ability to suppress.

Answer 14

true

Question 15

What are some of the key differences b/t Tregs and Tr1 cells?

Answer 15

• Tregs express FOXp3 and Tr1 do not
• Tregs act via direct interaction (cell-cell contact), while Tr1 act via IL10 in a systemic manner
• Tr1 cells are generated AFTER immune responses start to reduce the response, while Tregs are present BEFORE immune responses start to block initiation of immune responses

Question 16

MDSCs suppress which types of inflammatory conditions?

Answer 16

pre-existing inflammatory conditions (thus, acquire immunosuppressive functions AFTER an immune response has started)

Question 17

What are the 2 major molecules that MDSCs use to suppress T-cell responses?

Answer 17

NO (monocytic MDSCs) and arginase (granulocytic MDSCs)

Question 18

Which therapeutic strategies are MDSCs being tested for?

Answer 18

• promoting anti-tumor immune responses

- inhibiting immune responses for treatment of autoimmune disorders or transplant rejection

Question 19

Which protein is a potent inhibitor of the apoptosis-inducing surface antigen, Fas?

Answer 19

FLIP

Question 20

The surface antigen Fas does what?

Answer 20

When ligated by its ligand (Fas ligand), it initiates apoptosis in many tissues.

Question 21

What are MDSCs activated by?

Answer 21

cytokines like IFN-gamma

Question 22

Why are ALPS patients not as autoimmune prone as other patients?

Answer 22

because their Tregs, central tolerance, and Tr1 cells are all functional; ALPS patients just can’t get rid of T-cells that are no longer needed