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PABI 6100 Immunobiology- Exam > Tolerance > Flashcards

Tolerance Flashcards

1
Q

What supports hematopoiesis?

A
  • process by which HSCs differentiate into mature blood cells
  • stem cell niche in bone marrow supports
    > Perivascular niche- lines blood vessels
    > Endosteal niche- lines the bone
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2
Q

How do T cells develop?

A
  • T cell progenitors exit bone marrow at very immature stage > complete development in thymus
  • T cell precursors enter thymus in blood vessels at corticomedullary junction > DN cells express neither CD4/ CD8 markers
  • DN cells travel to subcapusular cortex > proliferate
  • DN cells travel to cortex > first express mature TCR/ upregulate both CD4/ CD8 markers (become DP cells)/ interact with cTECs
  • DP cells tested for ability of TCRs to bind MHC-peptide complexes on cTECs (cortical thymic epithelial cells)
    > bind too high affinity induced to die > negative selection
    > bind intermediate affinity survive > positive selection
  • as positively selected DP thymocytes mature > lose a marker/ become SP/ migrate to medulla > encounter mTECs
  • mTECs (medullary thymic epithelial cells) express proteins otherwise exclusively found in other organs > negatively select autoreactive T cells that could not be deleted in cortex
  • mature SP cells exit thymus as entered > via blood vessels at corticomedullary junction
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3
Q

What is tolerance?

A
  • many layers of protection imposed by immune system to prevent reaction of its cells/ antibodies against host components
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4
Q

What are the 3 mechanisms of tolerance?

A
  • Evasion- how location/ sequestration has a role in protecting some sites and the tissue-specific antigens found there from exposure to the immune system (passive process)
  • Elimination- mechanisms that remove many self-reactive lymphocytes before they can do damage (negative selection)
  • Engagement- cultivating certain self-reactive cells for protection of self-structures (regulatory phenotype)
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5
Q

How does the evasion mechanism of tolerance protect self-antigens from attack?

A
  • sequestration of antigens away from immune cells is an effective way to avoid self-reactivity
  • tissue-specific antigens in sequestered (immune-privileged) sites are rarely involved in peripheral tolerance
  • upon breaching of sequestered sites, newly exposed antigens are seen as foreign and attacked
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6
Q

What happens following trauma to the eye, and what does this suggest about the immune tolerance mechanism?

A
  • anterior chamber/ lens of eye are considered sequestered (immune-privileged) sites
  • after trauma to eye, sudden entry of immune cells > inflammation/ impaired vision
  • other eye may also become inflamed > likely due to sudden entry of recently activated immune cells recognizing newly discovered tissue-specific antigens
  • suggests concept of evasion/ sequestration of antigens may be oversimplified > may need active suppression of anti-self responses even in sites thought to be sequestered (partial barrier to immune cells)
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7
Q

What is central tolerance, and where does it occur?

A
  • fosters both destruction (elimination) and cultivation (engagement) of selected self-reactive lymphocytes
  • in primary lymphoid organs > bone marrow/ thymus
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8
Q

What is the first developmental step in central tolerance?

A

Elimination- removal of self-reactive lymphocytes (negative selection)
- most developing lymphocytes with receptors that recognize self-antigens are eliminated in PLOs > before allowed to mature
- negative selection > apoptosis of many developing lymphocytes with high-affinity TCRs/ BCRs that recognize antigens expressed in PLOs

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9
Q

What are the potential outcomes of central tolerance?

A
  • elimination > most self-reactive cells die via apoptosis
  • anergy > some self-reactive cells released from PLOs in anergic state > later deleted via apoptosis in periphery
  • engagement > some self-reactive cells are selected for survival during development > suppress/ regulate autoimmune responses in periphery
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10
Q

What are tTregs?

A
  • self-reactive cells (high affinity for self-antigens) selected for survival in thymus (engagement)
  • suppress/ regulate autoimmune responses to self-antigens in the periphery
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11
Q

How does the type of TCR/ MHC-peptide interaction in the thymus influence the fate of self-reactive T cells? (elimination vs engagement)

A
  • based on “hit and run” model > short, high-affinity but transient engagement of TCR/ MHC-antigen in thymus favours generation of regulatory cells > engagement
  • more sustained, high-affinity TCR engagement favours deletion of self-reactive lymphocytes > elimination
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12
Q

Like eliminated self-reactive T cells, tTregs have high affinity for self-antigens… what accounts for this difference in fate?
(elimination vs engagement)?

A
  • combination of both positive/ negative signaling events
  • interaction between CD28 (T-cells)/ CD80/86 (APCs)
  • interaction between CD40L (T-cells)/ CD40 (APCs)
  • presence of certain cytokines
  • engagement > short/ transient high-affinity interactions
  • elimination > more sustained high-affinity interactions
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13
Q

Despite central tolerance, some self-reactive lymphocytes can exit PLOs… how?

A
  • not all self-antigens expressed in PLOs where negative selection occurs (even with normal AIRE expression)
  • there is a threshold requirement for affinity to self-antigens before clonal deletion triggered > some weakly self-reactive cells survive
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14
Q

What is peripheral tolerance, and where does it occur?

A
  • multiple processes that limit/ redirect activity of self-reactive cells that exit PLOs despite central tolerance
  • mainly occurs in SLOs/ at tissue-site where relevant self-antigen is expressed
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15
Q

What is a tolerogen?

A
  • antigen that induces tolerance
  • context-dependent > same chemical can be immunogen/ tolerogen
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16
Q

How can interactions between mature naive lymphocytes/ antigen lead to tolerance? (periphery)

A
  • in specific locations/ microenvironments
    > SLOs or at tissue-site where relevant self-antigen is expressed
  • T cell engaged by a tolerogen/ in a tolerogenic setting may become a pTreg
17
Q

What are the 3 possible fates of a T cell engaged by a tolerogen/ in a tolerogenic setting? (peripheral tolerance)

A
  • elimination via apoptosis
  • anergy (unresponsiveness)
  • regulation > engagement leading to suppression (pTregs)
18
Q

What factors can induce mature naive T cells to express FoxP3/ become pTreg cells/ enter the regulatory pathway in the periphery?

A
  • lack of costimulation
  • presence of inhibitory cytokines or surface molecules
  • time and place of exposure
    > ex) fetal/ neonatal exposure > inhibitory responses
    > ex) route (oral vs subq) of antigen > tolerogenic/ immunogenic
19
Q

What are pTregs?

A
  • cells that mediate peripheral tolerance > generated outside PLOs
  • naive mature T cell engaged by a tolerogen > can become pTreg
20
Q

What happens when naive mature T cells bind foreign/ self-antigens in the periphery?

A
  • Foreign antigens > clonal selection/ activation/ differentiation into effector T cells that recognize foreign antigen
  • Self-antigens > 3 possible tolerogenic fates: apoptosis/ anergy/ regulation (pTreg)
21
Q

What immune cells work in the periphery to inhibit anti-self responses?

A
  • regulatory CD4+ T cells (tTregs/ pTregs)
  • regulatory CD8+ T cells
  • regulatory B cells (Bregs)
  • accessory cells with a regulatory function
    > APCs
    > Myeloid-Derived Suppressor Cells (MDSCs)
22
Q

What are some features of the immune cells that work in the periphery to inhibit anti-self responses?

A
  • all down-regulate immune activity when they engage
  • are all antigen-specific
  • regulatory CD4+ T cells are most well-characterized
  • act in SLOs and at sites of inflammation
23
Q

What are some features of regulatory CD4+ T cells?

A
  • can be generated in thymus (tTreg) or in periphery (pTreg)
  • express FoxP3/ CTLA-4/ CD25 (IL-2R α chain)
  • still engage antigen-MHC class II complexes through TCR > downregulate responses when do so
24
Q

How do regulatory CD4+ T cells inhibit anti-self responses (2x)?

A
  • inhibit immune responses via contact-dependent/ contact-independent mechanisms
  • Dependent- interaction between CTLA-4 (Tregs)/ CD80/86 (APCs) inhibits APC function
    > decreased CD80/86 expression
    > activation of IDO > creating an immunoinhibitory microenvironment > inhibit pro-inflammatory cytokines IL-6/ TNF-α
  • Independent > secretion of immune-inhibitory cytokines (IL-10/ TGF-β/ IL-35) that shut down nearby T cells/ APCs
    > due to high expression of CD25 (IL-2R α chain) > Tregs absorb IL-2 > prevent expansion of effector T cells
25
Q

CD4+ T regs suppress the immune response to what type of antigens?

A
  • both self and nonself antigens
26
Q

What is some evidence that CD4+ Tregs suppress the immune response to self-antigens?

A
  • NOD mice/ BB rats prone to develop autoimmune diabetes
  • inject with normal CD4+ T cells > delays onset of diabetes
  • shown that high CD25 expressing CD4+ T cell subset responsible for suppression of diabetes
  • population further characterized in mice expressing GFP fused to FoxP3 > GFP+ T cells transferred immunosuppressive activity
27
Q

What is some evidence that CD4+ Tregs suppress the immune response to non-self antigens?

A
  • pTregs are present in GALT > continuously exposed to gut microbes/ food-borne antigens
  • CD4+ Tregs may control allergic reactions against environmental substances/ responses to commensal microbes (normal gut flora)
28
Q

What is linked suppression?
- mediated by Tregs

A
  • Tregs can inhibit effector T cells with same antigen specificity/ T cells that recognize other antigens
  • occurs when both Treg/ effector T-cell recognizing another antigen interact with the same APC
    > results in inhibition of APC
    > results in inhibition of T-cell > through soluble inhibitory factors/ decommissioning of APC
  • when a single APC simultaneously interacts with T cells of different specificity > inhibitory signals meant for one can be transferred to both > leads to spreading of immune suppression to include other antigens
29
Q

What is an example of linked suppression?

A
  • Treg with specificity for A binds to APC displaying peptides A/B
  • Treg can inhibit both effector T cells with specificity for A/B (if they are bound to same APC)
  • Inhibits effector T-cell B even though different antigen-specificity
30
Q

What are some features of regulatory CD8+ T cells?

A
  • less well characterized/ fewer in number than CD4+ T regs
  • generated in periphery
  • express FoxP3/ CTLA-4/ CD8+ αα
  • express both high and low-affinity receptors for IL-2
  • best characterized are restricted to nonclassical MHC class I molecules
    > Qa-1 in mice/ HLA-E in humans
31
Q

What suggests that CD8+ Tregs regulate CD4+ T-cell responses to self-antigens to maintain peripheral tolerance?

A
  • mice engineered to lack Qa-1 restricted CD8+ Tregs developed aggressive autoimmune reactions against self-antigens
    > if mice lacked CD8+ Tregs > CD4+ responses led to autoimmunity
32
Q

What are some features of regulatory B cells?

A
  • no consensus phenotypic markers to characterize > diversity of surface markers
  • most produce high levels of inhibitory cytokine IL-10
    > B cells that only produce IL-10 are called B10 cells
33
Q

Studies have highlighted what in-vivo roles of regulatory B cells?

A
  • suppress inflammatory cascades associated with IL-1
  • mice with B cells incapable of secreting IL-10 > chronic TH1 activation/ worse autoimmune MS/ arthritis
34
Q

What does the fact that when mature B cells encounter most soluble antigens in the absence of T-cell help, they become anergic/ never migrate to germinal centers suggest?

A
  • maintenance of T-cell tolerance to self-antigens enforces B-cell tolerance to same antigens
35
Q

What are the regulatory functions of APCs?

A
  • downregulation of CD80/86 expression caused by tRegs
    > prevents APCs from stimulating T cells
    > encourages further production of Tregs when naive mature T cells interact with them
36
Q

How is decommissioning of APCs more effective than destruction in providing immunosuppression?

A
  • downregulation of CD80/86 prevents APCs from stimulating T cells
  • when naive, mature T cells interact with them > encourages further production of regulatory T cells
  • can bind to naive mature T cells > encourage them to become Tregs
37
Q

What are the regulatory functions of MDSCs?

A
  • group of heterogeneous immature myeloid cells
  • accumulate at sites of infection/ immune activity > suppress local antigen-specific T cell responses
  • secrete inhibitory compounds like IL-10/ IDO/ arginase-1/ iNOS
  • express immunosuppressive surface markers that negatively regulate T-cell proliferation (ex-PD-L1)

PABI 6100 Immunobiology- Exam (6 decks)

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