Lecture 27: Immunoregulation Flashcards
What is immune regulation important for?
the maintenance of immune responses to avoid excessive damage
What are the basic modes of regulation?
central e.g. repertoire selection
peripheral e.g. peripheral deletion, anergy, regulatory receptors, regulatory T cells
What is AIRE?
an important regulator involved in the expression of antigen from different sites of the body
not possible to express every single type
What is Autoimmune Polyglandular Syndrome (APS) Type 1 caused by?
lack of AIRE resulting in autoimmune reactions against endocrine glands
Why is central tolerance not perfect?
some clones may be able to escape selection and leave the thymus
Why is peripheral tolerance important?
potential formation of autoreactive B cells during somatic hypermutation
What do activation thresholds of B cells prevent?
stimulation by autoantigens e.g. B cells specific for the constant region of IgG -> rheumatoid arthritis
When does antigen sequestration occur?
in situations where escaped cells never see the antigens (antigen is never presented to T cells)
relevant for immune privileged sites
What can antigen sequestration result in?
instances such as sympathetic ophthalmia
What is the role of central tolerance during the formation of T and B cells?
help with removing autoreactive T cells
When does self presentation usually occur?
in the absence of inflammation
How does peripheral T cell tolerance occur?
removal of autoreactive T cells through apoptosis
How are T cells triggered to undergo apoptosis (deleted) during peripheral T cell tolerance (intrinsic)?
targeting the mitochondrial pathway of killing - intrinsic
lack of IL-2 and IL-7 signaling leads to upregulation of Bim which executes apoptosis
How are T cells triggered to undergo apoptosis (deleted) during peripheral T cell tolerance (extrinsic)?
through Fas/FasL pathway
also important in regular immune responses
How does anergy contribute to peripheral T cell tolerance?
renders cells unresponsive
involves biochemical signals to modulate TCR signalling
can be overridden with strong stimuli
How does anergy occur?
inhibition of TCR signalling through CbI-b
involved in the normal cessation of immune responses
What is the role of inhibition in regards to peripheral T cell tolerance?
response to chronic stress e.g. tumours and persistent viral infections
How does inhibition occur?
cytotoxic T lymphocyte associated protein 4 binds CD80 and CD86 (B7.1 B7.2) on APCs
inhibits activated T cells via decoy or intracellular activity
What is the role of PD-L1 and PD-L2?
important in modulating immune responses
PD-1 = programmed cell death 1
What does persistent stimulation of T cells lead to?
exhaustion which produces a stalemate situation where there is a virus/tumour-immune equilibrium
What is a proposed role of PD-1?
role in the establishment and reversal of HIV latency
What can peripheral tolerance manage?
detection of self-antigen in the periphery in multiple ways
How can deletion of self-reactive T cells occur?
via the Fas-FasL pathway
How can autoreactive cells be rendered anergic?
when stimulated with antigen under
non-inflammatory conditions
How can autoreactive or overactive T cells be inhibited?
via engagement with inhibitory checkpoint markers (CTLA4 and PD1 as molecules of interest)
What can manipulation of checkpoint blockades open up?
strategies for managing chronic infections and anti-tumour responses
Where can Treg cells be generated? Which cells are committed to the Treg lineage?
in the thymus or in the periphery
thymocytes at the cusp of negative selection can be committed to the Treg lineage
What is an indicator of Treg cells?
transcription factor Foxp3
What are IL-2 and TGF-beta important for?
the induction of Foxp3
What is the dual role of TGF-beta?
an anti-inflammatory cytokines which is also involved in the stimulation of naive T cells which dictates the inflammatory nature of the cell depending on the presence of absence of IL-6
What happens if there is no IL-6 present during stimulation of naive T cells?
presentation of microbiota derived antigens by retinoic acid producing DCs promote Treg formation since there is no IL-6 present to suppress retinoic acid
What happens if there is IL-6 present during stimulation of naive T cells?
suppresses retinoic acid and favours development of Th17
What are the effector functions of Treg cells?
can act on other T cells or APCs
suppressive cytokines and secreted molecules, cytolysis, metabolic disruption, targeting DCs by other mechanisms
