Levings Content

Question 1

immune tolerance

Answer 1

• state of unresponsiveness to an antigen

Question 2

antigens that should not become targets of effector cells (2)

Answer 2

1. self-antigens
2. non-harmful foreign antigens

Question 3

self-antigens (3)

Answer 3

• systemic (eg. RBC)
• tissue specific
• developmental stage specific

Question 4

non-harmful foreign antigens examples (4)

Answer 4

• allogeneic fetus
• commensal bacteria
• food
• inhaled antigens

Question 5

how are TCRs and BCRs made

Answer 5

• somatic recombination to make random receptors

Question 6

what occurs when tolerance goes wrong (3)

Answer 6

• autoimmunity
• allergy (to non-harmful antigens)
• auto-inflammation

Question 7

what occurs when tolerance works too well (2)

Answer 7

• cancer
• persistent infections

Question 8

what are some clinical uses for tolerance

Answer 8

• induce tolerance to transplanted cells and organs/foreign tissues

Question 9

two layers of tolerance (2)

Answer 9

• central
• peripheral

Question 10

central tolerance (3)

Answer 10

• bone marrow (B cells)
• thymus (T cells)
• regulates tolerance to self by removing potentially self-reactive immature lymphocytes

Question 11

peripheral tolerance (2)

Answer 11

• tolerance in places other than BM and thymus
• regulates tolerance to self and non-harmful foreign antigens

Question 12

central T cell tolerance (2)

Answer 12

• T cells that bind antigens too loosely do not pass
• T cells that bind antigens too strongly do not pass

Question 13

AIRE (2)

Answer 13

• thymic epithelial cells express this TF
• allows expression of as many genes as possible in thymus

Question 14

AIRE genetic mutation

Answer 14

• results in severe autoimmune disease as process if negative selection is defective

Question 15

how does AIRE work

Answer 15

• as a TF, it worked by controlling transcription

Question 16

thymic “mimetic” cells (3)

Answer 16

• express peripheral tissue antigens
• mirror extra-thymic cell types but maintain thymic epithelial cell identity
• allows for negative selection of all cell types in the thymus

Question 17

AIRE and Treg development

Answer 17

• AIRE-deficiency results in T cell escape from negative selection AND defective Treg cell development

Question 18

thymic development of FOXP3+ Tregs (2)

Answer 18

• immature CD4+ T cells that have medium-high affinity for self-antigens take on FOXP3-CD25+ Treg cell precursor phenotype in a TCR dependent manner
• FOXP3+ Treg cell develops in a TCR independent manner, but relies on IL-2 and IL-15

Question 19

how accurate is central T cell tolerance (2)

Answer 19

• not perfect; some self-reactive T cells escape negative selection
• to handle this, peripheral tolerance is employed as a second level of control

Question 20

T cell activation signals (3)

Answer 20

signal 1: antigen (presence, absence, affinity)
signal 2: co-stimulation vs co-inhibition
signal 3: cytokines

Question 21

what is peripheral T cell tolerance controlled by

Answer 21

• quality of T cell activation

Question 22

major mechanisms of peripheral tolerance (3)

Answer 22

• deletion
• anergy
• suppression

Question 23

peripheral tolerance: deletion (2)

Answer 23

• activation induced cell death
• Fas/FasL pathway critical for deletion of T cells that have been stimulated repeatedly in periphery by antigen

Question 24

result of mutations of Fas/FasL

Answer 24

• lymphadenopathy (swelling lymph nodes) and autoimmunity

Question 25

what is an analogous mutation in humans of the Fas/FasL mutation in mice (2)

Answer 25

- autoimmune lymphoproliferative syndrome - defective lymphocyte apoptosis, lymphocyte accumulation, anemia, and thrombocytopenia (low platelet count)

Question 26

peripheral tolerance: anergy/exhaustion (3)

Answer 26

- lack of responsiveness and inability to perform any activity - results from lack of signal 1 or lack of signal 2 as cell will be half activated and unable to have effector function - lacks positive or negative signal

Question 27

anergy vs exhaustion

Answer 27

- phenotypically similar hyporesponsive states, but different characteristics behind state

Question 28

anergy vs exhaustion: anergy characteristics (3)

Answer 28

- low transcription of cytokines and cell cycle genes - gene expression enforces the anergic phenotype - hyporesponsiveness even if they receive a full activation signal in the future

Question 29

anergy vs exhaustion: exhaustion characteristics (3)

Answer 29

- caused by strong and sustained signals - fail to secrete cytokines, lyse target cells, or proliferate effectively - sustained expressed of co-inhibitor molecules

Question 30

positive vs negative signal 2 (3)

Answer 30

- can be used in therapies to alter T cell responses - therapeutic manipulations to induce tolerance - describe co-stimulation that can either be stimulatory or inhibitory

Question 31

peripheral tolerance: suppression

Answer 31

- by regulatory cells

Question 32

positive vs negative signal 2: CTLA-4 (2)

Answer 32

- important Treg mechanism of suppression - activation-induced CTLA-4 expression will terminate the immune response

Question 33

positive vs negative signal 2: PD1

Answer 33

- reduces TCR signaling, cytokine production, and target cell lysis

Question 34

peripheral tolerance: regulatory cells

Answer 34

- immune cells which actively stop immune response

Question 35

regulatory cell examples and most known examples (2)

Answer 35

- many different types: macrophages, B cells, NK cells, T cells, etc - most is known about CD4+ Treg cells which express FOXP3 TF

Question 36

FOXP3+CD4+ Treg cells (3)

Answer 36

- defined by FOXP3 and CD25 expression - do not produce T-cell derived cytokines - suppress many diff types of cells and immune responses

Question 37

how does the proportion of Treg cells change throughout your life (2)

Answer 37

- throughout life, proportion of effector cells increases due to expansions after infection, leading the Treg proportion to become smaller (~1-3%) - as babies, Tregs are very important for tolerance and are present at high proportions

Question 38

how were Tregs discovered (3)

Answer 38

- classification of IPEX disease - discovery that CD25+CD4+ T cells control autoimmunity in mice - link between FOXP3, IPEX, and CD4+CD25+ T cells was made

Question 39

IPEX disease (3)

Answer 39

- multi-organ autoimmunity - due to X-linked mutations in FOXP3 gene - caused by lack of Treg cells, which are essential to tolerance development

Question 40

cell therapy with FOXP3+ Tregs (2)

Answer 40

- Tregs can work for drug therapy as they can rescue phenotypes that lack Tregs with a single injection - Tregs can proliferate and turn other cells in Tregs

Question 41

mechanism of FOXP3+ Treg action (3)

Answer 41

- bystander suppression by reducing APC effectiveness: effects all cells in local environmental even if antigen isn't specific to Treg - infectious tolerance: can turn other CD4+ T cells into Treg cells - secretes anti-inflammatory cytokines

Question 42

FOXP3 locus

Answer 42

- Treg cells can be distinguished from T cells as their CNS2 locus is not methylated

Question 43

peripheral development of FOXP3+ Tregs (2)

Answer 43

- evolution with placental mammals (carry fetus within body); likely evolved to protect baby from own immune system - oral tolerance and the microbiome