Week 9 - Immune Regulation Flashcards
Loss of Tolerance
Has life threatening consequences
Loss of tolerance to self
- destruction of self tissues
- autoimmune disease
Loss of tolerance to innocuous non-self
- e.g. inhaled antigen such as pollens
- allergy
Development of Tolerance
Development of tolerance to cancer
Development of tolerance to pathogens
How does the Host Avoid Destruction by T and B Cells?
Central tolerance
Avoidance/barriers/ignorance
- skin
- sequestration of antigen
Regulation/suppression
- by regulatory cells
Destruction (deletion)
- clonal deletion
Incapacitation
- turn off reactive cells
Skewing
- become a different cell
Central Tolerance
Primary lymphoid organs (bone marrow and thymus)
E.g.
- self antigen in BM or thymus -> deletion of high affinity self Ag lymphocytes
- lymphoid maturation of clones weakly responsive to self Ag
Peripheral Tolerance
Secondary lymphoid organs (lymph nodes and spleen)
E.g.
- self antigen in peripheral tissues -> regulation or anergy of self Ag specific lymphocytes
- immune response to foreign Ag
Central B Cell Tolerance in the BM
Works by:
1. Deletion
- death by apoptosis
2. Anergy
- long term inactivation
3. Receptor Editing
- reactivation of V(D)J recombination
- B cell with receptor for non-self antigen
Central T Cell Tolerance
Works by:
1. Death by Neglect
- no TCR interation with self antigen in MHC on thmyic epithelial cells or dendritic cells -> apoptosis
2. Negative Selection
- double positive TCR - high affinity for self antigen -> apoptosis
3. Positive Selection
- single positive TCR - low affinity for self Ag -> migrate to LN and spleen
Regulation of Peripheral Autoreactive T Cells
- Ag Sequestered -> clonal ignorance
- APC, MHC/Ag + Costimulation -> autoimmunity
- APC, MHC/Ag with No Costimulation -> clonal anergy
- Suppression
Cells that Suppress the Immune Response
CD4+CD25+ regulatory T cells (Treg)
CD4+ Th2 cells
CD4+ Th3 cells
M2 Macrophages
Myeloid derived suppressor cells
Immature dendritic cells
Regulatory T Cells (Tregs)
CD4+ CD25+ (IL-2 receptor a chain)
FoxP3+ (forkhead box P3 = nuclear transcription factor)
- master regulator in the development of regulatory T cells
Mediated by cytokines:
- transforming growth factor beta 1 (TGFb-1)
- IL-10
Role of Cytokines in Suppression
IL-10 inhibits functions of APCs: IL-12 secretion, B7 expression
TGF-B inhibits T cell proliferation
IL-4 inhibits actions of IFN-g
IL-10, TGF-B inhibit macrophage activation
Immature Dendritic Cells
Express low levels of MHC I / II, co-stimulatory molecules (CD40, CD80, CD86)
Not activated in a ‘dangerous setting’ (won’t drive T cell responses) - take up self antigen
Do not activate effector T cells
Secrete IL-10
Directly responsible for inducing Tregs
Prevents autoimmunity
NK Cell and Dendritic Cell Association
Activate each other
DCs express ligands for NKp30
NK cells can kill (immature) DC
Stop DCs from activating T cells
M1 Macrophages
Pro-inflammatory
Anti-microbial
Anti-tumour function
Phagocytes
Present antigen to T cells
Activate T cells
M2 Macrophages
Wound healing, angiogenesis
Promote tumour growth
Reported to be in tumours
Present antigen to T cells
Suppress T cell function
What Parts of the Body Can the Immune System Not Recognise Self Antigens?
Brain
Eye
Testis
Uterus (fetus)
Sympathetic Opthalmia
Antigens hidden (sequestered) from the immune system
Injury in one eye shows up in other healthy eye
Mediated by T cells
Sympathetic Opthalmia Steps
Trauma to one eye results in release of sequestered intraocular protein antigens
Released intraocular antigen is carried to lymph nodes and activates T cells
Effector T cells return via bloodstream and encounter antigen in both eyes
Damage Associated Molecular Patterns
DAMPs are nuclear or cytosolic self proteins
Released when tissues are injured
Examples:
- high-mobility group box 1 (HMGB1) - TLR2 and TLR4
- DNA not in nucleus or mitochondria -TLR9
- damaged RNAs - TLR3
Checkpoint Molecules
Negative immune regulatory molecules
Prevent excessive inflammation and dampen responses that could induce autoimmunity
Mostly target T cells
Tumour cells take advantage of these pathways to inactivate anti-tumour T cells
How do Checkpoint Molecules Work?
Programmed cell death protein-1 (PD-1) is expressed on activated T cells
Programmed cell death ligand (PD-L1) on APCs
APC binds T cells with this ligand -> inhibits T cell proliferation
Checkpoint Molecule - Adenosine
Naturally occurring purine nucleoside
From breakdown of adenosine triphosphate (ATP) = primary energy source for cells
Ectonucleoside triphosphate diphosphohydrolase-1 (CD39)
- converts adenosine triphosphate (ATP) to adenosine diphosphate (ADP)
- converts ADP to adenosine monophosphate (AMP)
Ecto-5’-nucleotidase (CD73)
- converts AMP to adenosin
Effects of Adenosine Binding to A2A and A2B Receptors - T cells
↓ T cell proliferation
↓ T cell cytokine production
Effects of Adenosine Binding to A2A and A2B Receptors - DCs
Prevent DC maturation
↓ DC pro-inflammatory cytokines
↑ DC suppressive cytokines
