14- Immunological Tolerance

Question 1

What is immunological tolerance?

Answer 1

non-responsiveness to specific antigens (ex. self-tissues, foods, pregnancy, etc.)

Question 2

Relationship between tumors and immunological tolerance

Answer 2

Anti-tumor immunity is often impaired by immunological tolerance provoked by the tumor environment.

Question 3

What are the 2 methods of inducing tolerance?

Answer 3

(1) Central tolerance: based on the elimination of T cells that are reactive to antigens present in the thymus (self-antigens)
(2) Peripheral tolerance: Treg + Myeloid Derived Suppressor cells + anergy due to insufficient stimulation

Question 4

MDSCs

Answer 4

Myeloid Derived Suppressor Cells:

A group of myeloid cells which become potent immunoregulatory cells when exposed to inflammatory cytokines such as IFN-gamma, and kill activated T cells to prevent further stimulation.

Question 5

Thymic Negative Selection + AIRE

Answer 5

The AIRE gene enables thymic stromal cells to express non-thymic genes and present self antigens to developing thymocytes. If cells have a high affinity , they are eliminated.

Question 6

Where are Tregs created?

Answer 6

Hassall’s corpuscles are the site for Treg generation

Question 7

APS

Answer 7

Autoimmune Polyendocrine Syndrome

Loss of functions of AIRE gene lead to the destruction of endocrine organs by antibodies and lymphocytes.

Question 8

nTregs

Answer 8

Generated in the thymus.

These cells impose suppression of T cells, and other immune cells.

Question 9

iTregs

Answer 9

Inducible Tregs

Induced by antigen presenting cells that are present in the mucosal environment such as intestine. Easily manipulated by the environment and pathogens.

Question 10

Tr1 cells

Answer 10

These cells produce immunosuppressive cytokine IL-10.

Induced to form by IL-10 or TGF-B and IL-27. THEY ARE NOT Foxp3+.

Question 11

IPEX

Answer 11

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked.

Failure of peripheral tolerance due to loss of Foxp3 function. Patients will die without aggressive treatment.

Question 12

Clonal Anergy + CD28

Answer 12

When naïve t cells are presented antigens in the absence of CD28, cells are partially activated and become anergic (non-responsive)

Question 13

CTLA-4

Answer 13

Expressed by T cells after activation and competes with CD28 for B7 binding (and will ultimately win due to a higher binding affinity). Also recruits signaling molecules which suppress TCR signaling and antigen activation.

Question 14

Clinical application of CTLA4

Answer 14

CTLA-4 can be used as an inhibitor of co-stimulation, which significantly improves the frequency of graft versus host (GVH) disease after bone marrow transplants.

Question 15

What can happen as a result of knocking-out IL-10 or IL-2?

Answer 15

Inflammatory Bowel Disease (IBD)