D4. Immune regulation Flashcards
what do Treg cells do
what types of immune diseases are induced by: Th1, Th2, Th17
what is novel Th group induced by/ inhibited by
Prevent cytokine storm
Th1 induce autoimmunity: IBD, MS, diabetes, etc
Th2 induce allergies
Th17 induce inflammation
Novel Th group induced by IL-17 and TGFβ development inhibited by IFN-y and IL-4
Define Treg cells
Immunosuppressive T cells with cytokine profiles distinct from either Th1 or Th2 T cells
Removing Treg or thymus develops what types of pathology
- Th1, Th2, Th17 promote
- what could prevent this
-
autoimmunity & immunodeficiency
- promote: cell mediated or humoral immune responses
- Transfer of normal lymphocytes
Do Treg prevent initial Tc reaction?
The effect of Treg pops in vitro
T regs do not prevent initial T cell activation but inhibit a sustained response and prevent chronic immunopathology
Treg populations are anergic in vitro
Lack characteristics of both Th1 and Th2
Inhibit cellular responses
what do Treg cells secrete?
- Growth is dependent on
Secrete +++IL-10, +++TGF-β and + IL-4
- IL-2 and IL-15
What are the 4 basic mechanisms Treg uses to suppress immune responses
- Modulation of APC maturation & function
- killing of target cells
- disruption of metabolic pathways
- production of anti-inflammatory cytokines
Where do Treg cells come from
2 theories
Treg = separate lineage derived from the thymus
- Mice thymectomised 3 days after birth develop fatal autoimmune disease
2.derived from naïve precursors in the periphery
- CD4+CD25+ cells are generated from naïve precursors, undergo limited expansion in vivo, fail to produce IL-2 in vitro.
Athymic mice develop Treg
Treg selection in thymus
determined by the affinity of the Tc for the self-peptide-MHC
very strong signals (self Ag) = apoptotic death
weak signal = effector cell
Intermediate signal = Treg
describe nTreg
- what is transcription factor
- Mutations in transcription factor results in
- Transduction of Foxp3 results in what
= naturally occurring Tregs
Educated in thymus during -ve selection & exit as regulatory population expressing FoxP3 3 days after birth
Foxp3 transcription factor
Mutations in Foxp3 result in autoimmune & inflammatory diseases
Humans with mutations in Foxp3 suffer from a severe and rapidly fatal autoimmune disorder known as Immune dysregulation, Polyendocrinopathy, Enteropathy X-linked (IPEX) syndrome
Transduction of Foxp3 into naïve cells induces suppressor function
what is Treg-induced suppression dependent on
contact dependent
- il-2 is required for suppression
(CD25 is the IL-2Ra chain)
GITR is involved but not known how
Describe the 2 2 different populations of
Tr1 cells - Induced by IL-10 - Do not express CD25 or Foxp3 - Mediate suppression through secretion of IL-10 2. Induced Treg - Induced by TGFβ - Vitamin A (retinoic acid) also important - Express Foxp3 and upregulate CD25 Mediate suppression through TGFβ
What are the 3 major types of Treg
- nTreg, iTreg (Th3), iTreg (Tr1)
Treg cells develop when
when stimulated with immature DC (not mature)
IL-10 inhibits DC maturation & promotes development of Treg cells
Immunosuppressant 1a,25-dihydroxyvitamin D3 inhibits DC maturation and thus promotes development of Treg cell
Role of IL-10
Acts on activated macrophages to return system to resting state as pathogens are eradicated
Inhibits production of IL-12 and TNF by activated macrophages
- Downregulates IFN-y secretion and Th1 responses
Inhibits expression of costimulators and class II MHC
- Inhibits T cell activation and cell-mediated immune responses
Stimulates proliferation of B cells
- IL-10 KO get IBD
- Epstein-Barr virus contains IL-10 gene homolog (ensures survival)
Do Treg recognise self,
During thymic development self reactive T cells are either deleted or anergic
Normally no self reactive T cells
Self reactive Treg have been shown in diabetes and EAE
Treg also recognise non self Ag such as bacteria, fungi and protozoa
As for conventional T cells self reactive T cells are the exception rather than the rule
((don’t normally get self reactive effector Tc (eliminated during self deletion)))
Is suppression by Treg antigen-specific?
Activation of Treg in Ag specific but suppression of target Th cells is antigen dependent but does not need to be antigen specific
(Treg must first be activated by Ag to become suppressive)
How do Treg know which Th cell to suppress?
Need to know which is a bad (self-reactive) and good (pathogen-specific) T cell.
Cross-regulation/Effector class regulation
- Antigen-specific interaction between Treg, Ag specific-T cell and APC
- Treg “educate” APC
TCR signal strength
- Treg suppress low affinity TCR
- Increased inflammatory signal decrease Treg activity
Feedback control
- Control the magnitude of Ag-specific response
What are the functions of Treg
Prevention of autoimmune disease
- establishing and maintaining immunologic self-tolerance
Suppression of allergy and asthma
Induction of (oral) tolerance to dietary antigens and commensal bacteria
Induction of maternal tolerance to the foetus
- Increased likelihood of miscarriage
Suppression of pathogen-induced immunopathology
Regulation of T cell activation
