Cellular Basis

Question 1

Define immunological tolerance.

Answer 1

• non-responsiveness to specific antigens
• tolerant of self, food, environment
• homeostasis (enhanced tolerance = recurrent infection; defective tolerance = immune response)

Question 2

What are the 2 methods of gaining tolerance?

Answer 2

• central

- peripheral

Question 3

Define central tolerance.

Answer 3

• thymic maturation
• based on negative selection of T cells that react to self-antigens presented in the thymus or B cells that react to self-antigens in the bone marrow

Question 4

What are 3 methods of gaining peripheral tolerance?

Answer 4

1. Tregs
2. MDSCs
3. Clonal anergy

Question 5

Define regulatory T cells.

Answer 5

suppress the immune response

Question 6

Define MDSCs.

Answer 6

myeloid-derived suppressor cells = firefighters

• kill activated T cells to prevent further stimulation
• recruited to a site of infection by inflammatory cytokines (IFNg)

Question 7

Define clonal anergy.

Answer 7

T cells do not induce an immune response because they are not activated in the proper way. This can be due to a lack of appropriate co-stimulators

Question 8

Define AIRE.

Answer 8

autoimmune regulatory element (?)

• transcription factor that allows thymic mTECs to produce non-thymic self peptides to test for autoimmunity
• those T cells with high affinity => apoptosis
• those T cells with low affinity => leave as naive T cells
• those T cells with intermediate affinity => become nTregs in the Hassall’s Corpuscles

Question 9

Describe Treg differentiation in the thymus.

Answer 9

• those T cells with intermediate affinity to self-antigens=> become nTregs in the Hassall’s Corpuscles
• induction of Foxp3
• requires IL2

Question 10

Describe what a loss of AIRE leads to.

Answer 10

APS or APECED

• loss of central tolerance
• lots of autoimmune disorders
• particular autoimmunity against endocrine organs

Question 11

Describe the function of MDSCs.

Answer 11

• initially found to infiltrate solid tumors; now found in adipose cells
• activated by IFNg
• produce anti-inflammatory cytokines

Question 12

What are MDSCs used for in treatment?

Answer 12

• anti-MDSC antibodies used in anti-tumor treatment (suppression of MDSCs => enhance immune response)
• MDSCs used in autoimmune disorders or transplants

Question 13

Define nTregs.

Answer 13

• generated in the thymus
• suppress other T cells
• express foxp3 and CD25 (IL2Ra)
• antigen-specificity is limited to self-antigens (can’t be used to suppress immune responses to food/environment)

Question 14

Define iTregs.

Answer 14

• generated in peripheral lymphoid organs
• antigen-specificity includes food, environment, commensal bacterial peptides, and tumors
• requires both TGFb and IL2, and Foxp3 expression
• inhibited by IL6
• induced by APCs in the mucosa
• cofactors required include Vitamin A and Vitamin D

Question 15

Define Tr1 cells.

Answer 15

• induced by TGFb and IL27
• do NOT express Foxp3
• produce IL10
• if there is lots of IL10 in the environment, they can be induced
• IL10 is upregulated by Vitamin D => increased Tr1 generation

Question 16

Describe IPEX.

Answer 16

immune dysregulation polyendocrinopathy enteropathy Xlinked (?)

• lack of peripheral tolerance
• lack of Foxp3 => no Tregs
• systemic autoimmunity
• leads to death if not treated with bone marrow transplant within first year

Question 17

What causes clonal anergy?

Answer 17

• lack of CD28 costimulation by CD80/86 on APCs
• causes partial activation that leads to degradation of signaling molecules required for activation
• cell can no longer be activated
• therefore, when an antigen is presented by a tumor or a regular cell, the T cell will become anergic (this is good - if antigen is on self; bad if antigen is on tumor)

Question 18

What is CTLA-4?

Answer 18

• expressed after a T cell is already activated to prevent further stimulation
• competes with CD28 for binding to B7 (CD80/86)
• has higher affinity for B7 (Basically a CD28 cockblocker)
• recruits suppressor molecules for TCR; blocks antigen activation

Question 19

What roles does CTLA-4 play?

Answer 19

• natural: increased expression after T cell activation to prevent runaway T cell proliferation and stimulation
• immune homeostasis (knockout leads to autoimmune disorders)
• Tx for cancers (anti-CTLA4 antibodies causes enhanced immune response)
• Tx for autoimmune disorders (CTLA-4-Ig inhibits CD28 from the outside of the cell by binding to B7 on the T cells)

Question 20

Describe the mechanism for how MDSCs work.

Answer 20

1. immune response typically involves Th1 and CD8, which produce IFNg
2. IFNg is proinflammatory and recruits MDSCs to the site of infection
3. IFNg activates MDSCs to differentiate into suppressor cells
4. MDSCs generate NO (apoptosis) and arginase (cell cycle arrest) to suppress T cells

Question 21

Compare Tregs and MDSCs.

Answer 21

• MDSCs are firefighters (recruited to site), while Tregs are police officers (constantly present)

Question 22

What is the role of IL2?

Answer 22

maintenance and induction of nTregs

Question 23

What is the role of the Hassall’s corpuscle?

Answer 23

• located in medulla of thymus
• location of nTregs differentiation
• provides TSLP (thymic stromal lymphopoietin) for nTreg differentiation

Question 24

What is unique about TGFb being involved in the iTreg differentiation process?

Answer 24

• typically, TGFb is proinflammatory, when in conjunction with IL6 (forms Th17)
• however, in the presence of IL2 => iTregs

Question 25

What is the relationship between Th17 and iTregs?

Answer 25

opposite effects

Question 26

What is the effect of loss of TGFb?

Answer 26

• loss of effector cells (Th17)

- loss of regulatory cells (iTreg)