Levings Content Flashcards
immune tolerance
- state of unresponsiveness to an antigen
antigens that should not become targets of effector cells (2)
- self-antigens
- non-harmful foreign antigens
self-antigens (3)
- systemic (eg. RBC)
- tissue specific
- developmental stage specific
non-harmful foreign antigens examples (4)
- allogeneic fetus
- commensal bacteria
- food
- inhaled antigens
how are TCRs and BCRs made
- somatic recombination to make random receptors
what occurs when tolerance goes wrong (3)
- autoimmunity
- allergy (to non-harmful antigens)
- auto-inflammation
what occurs when tolerance works too well (2)
- cancer
- persistent infections
what are some clinical uses for tolerance
- induce tolerance to transplanted cells and organs/foreign tissues
two layers of tolerance (2)
- central
- peripheral
central tolerance (3)
- bone marrow (B cells)
- thymus (T cells)
- regulates tolerance to self by removing potentially self-reactive immature lymphocytes
peripheral tolerance (2)
- tolerance in places other than BM and thymus
- regulates tolerance to self and non-harmful foreign antigens
central T cell tolerance (2)
- T cells that bind antigens too loosely do not pass
- T cells that bind antigens too strongly do not pass
AIRE (2)
- thymic epithelial cells express this TF
- allows expression of as many genes as possible in thymus
AIRE genetic mutation
- results in severe autoimmune disease as process if negative selection is defective
how does AIRE work
- as a TF, it worked by controlling transcription
thymic “mimetic” cells (3)
- 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
AIRE and Treg development
- AIRE-deficiency results in T cell escape from negative selection AND defective Treg cell development
thymic development of FOXP3+ Tregs (2)
- 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
how accurate is central T cell tolerance (2)
- not perfect; some self-reactive T cells escape negative selection
- to handle this, peripheral tolerance is employed as a second level of control
T cell activation signals (3)
signal 1: antigen (presence, absence, affinity)
signal 2: co-stimulation vs co-inhibition
signal 3: cytokines
what is peripheral T cell tolerance controlled by
- quality of T cell activation
major mechanisms of peripheral tolerance (3)
- deletion
- anergy
- suppression
peripheral tolerance: deletion (2)
- activation induced cell death
- Fas/FasL pathway critical for deletion of T cells that have been stimulated repeatedly in periphery by antigen
result of mutations of Fas/FasL
- lymphadenopathy (swelling lymph nodes) and autoimmunity
what is an analogous mutation in humans of the Fas/FasL mutation in mice (2)
- autoimmune lymphoproliferative syndrome
- defective lymphocyte apoptosis, lymphocyte accumulation, anemia, and thrombocytopenia (low platelet count)
peripheral tolerance: anergy/exhaustion (3)
- 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
anergy vs exhaustion
- phenotypically similar hyporesponsive states, but different characteristics behind state
anergy vs exhaustion: anergy characteristics (3)
- 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
anergy vs exhaustion: exhaustion characteristics (3)
- caused by strong and sustained signals
- fail to secrete cytokines, lyse target cells, or proliferate effectively
- sustained expressed of co-inhibitor molecules
positive vs negative signal 2 (3)
- 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
peripheral tolerance: suppression
- by regulatory cells
positive vs negative signal 2: CTLA-4 (2)
- important Treg mechanism of suppression
- activation-induced CTLA-4 expression will terminate the immune response
positive vs negative signal 2: PD1
- reduces TCR signaling, cytokine production, and target cell lysis
peripheral tolerance: regulatory cells
- immune cells which actively stop immune response
regulatory cell examples and most known examples (2)
- many different types: macrophages, B cells, NK cells, T cells, etc
- most is known about CD4+ Treg cells which express FOXP3 TF
FOXP3+CD4+ Treg cells (3)
- defined by FOXP3 and CD25 expression
- do not produce T-cell derived cytokines
- suppress many diff types of cells and immune responses
how does the proportion of Treg cells change throughout your life (2)
- 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
how were Tregs discovered (3)
- 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
IPEX disease (3)
- multi-organ autoimmunity
- due to X-linked mutations in FOXP3 gene
- caused by lack of Treg cells, which are essential to tolerance development
cell therapy with FOXP3+ Tregs (2)
- 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
mechanism of FOXP3+ Treg action (3)
- 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
FOXP3 locus
- Treg cells can be distinguished from T cells as their CNS2 locus is not methylated
peripheral development of FOXP3+ Tregs (2)
- evolution with placental mammals (carry fetus within body); likely evolved to protect baby from own immune system
- oral tolerance and the microbiome
