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)))