Regulatory T cells Flashcards
What is self/non-self discrimination?
The role of the normal immune system is to Eliminate/ control microbes with limited damage. Its able to discriminate between Self Antigen (host) and Foreign (non self microbe antigen)
successful self discrimination is when self antigen is detected by a self reactive T cell but there is immunological unresponsiveness and therefore self-tolerance.
Unsuccessful self tolerance is when the self-reactive T cell recognise self antigen as the hosts so the immune system attacks self tissues and organs = Autoimmunity
How is self- tolerance achieved?
Central tolerance also known as negative selection which is to eliminate T and B cells which recognise self antigens in the thymus .. They do this by clonal deletion.
However some self reactive T cells escape central tolerance so they go through peripheral tolerance which is to eliminate cells recognising tissue specific self antigen expressed in peripheral lymphoid tissue e..g lymph nodes or the spleen
This is done by anergy (removing T cell responses), apoptosis deletion or suppression by regulatory T cells.
What are Regulatory T cells?
The regulatory T cells formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Tregs are immunosuppressive and generally suppress or downregulateinduction and proliferation of effector T cells.[1] Tregs express the biomarkers CD4, FOXP3, and CD25 and are thought to be derived from the same lineageas naïve CD4 cells.
Treg cells produce markers for identification. Give examples.
CD25:
- It is linked to IL-2 (produce by DC cells during costimulation)
- CD25 is the high affinity IL-2 receptor unregulated during T cell activation and also unregulated more IL-2 production
- However, the problem with using this marker is that it is unregulated on effector T cells swell as being on T regulatory cells so it is difficult to determine what is present
FoxP3:
- FoxP3 is a master regulator of Treg development and function. It was identified in mice (Scurfy) which is when there is a X Chromosome mutation involving FOXP3. It causes autoimmunity and inflammation. FoxP3 is crutial for Treg cell development and function however the problem in humans is that activated non regulatory T cells can express FoxP3 – so it is a non specific marker .
What is the problem associated with faulty FoxP3?
IPEX syndrome (Immune dysregulation, Polyendocrinopathy, Enteropathy (inflammation in gut), X-linked)
It is a Rare genetic disease – 15 cases globally with the defective gene being FOXP3. It means that the body cannot produce nTregs ((CD4+CD25+Foxp3+)
Symptoms include:
- persistent severe diarrhoea
- insulin-dependent diabetes
- dermatitis
- thyroiditis
- haemolytic anaemia
This is autoimmunity
What are the different types of Treg cells
Thymus-derived Treg cells (tTreg)/nTreg naturally derived:
- These cells develop in thymus from the CD4+ thymocyte in utero and are present from birth
- The main type is CD4+CD25+Foxp3+ nTreg cells
- They represent 5-10% of CD4+ T cells in peripheral circulation
- They are designed to suppress/regulate and are specific for self Ags
Peripherally-derived Treg cells (pTreg) or iTregs (inducible):
- generated in the periphery lymphoid organs (PLOs) under various tolerogenic conditions during/after inflammatory reactions.
- They arise from naïve CD4+ TH cell
- Types include:
o CD4+CD25+Foxp3+ pTreg cells (arise from naïve CD4+ T cells)
(propagated from animals via oral tolerance)
o TGF--secreting pTreg cells (Th3)
(induced experimentally: Ag stimulation of naive T cells + IL-10 (high levels)(mucosa))
o IL-10-secreting Treg cells (Tr1) - induced experimentally: Ag stimulation of naive T cells + IL-10 (high levels)(mucosa) (FoxP3- Tregs)
pTregs also acquire regulatory function following Ag stimulation in the presence of certain cytokines
To which stage can Treg cells suppress
- Suppress at induction of T cell activation
o in peripheral lymphoid organs (PLOs) - Suppresison during the effector phase
o In various peripheral tissues - Suppression of target cell activation, proliferation and effector production e..g cytokine production
Which cells can Tregs suppress?
Innate Immune cells
- Inhibit DCs, macrophages, NK/NKT cells, ,ast cells
- Involved on tissue repair and resolution via TGF-B
Adaptive Immune cells
- Suppress CD4 and CD8 proliferation
- Suppress differentiation into TH1, TH2 and TH17
- Induce apoptosis of responding T cells
- Suppress B cell activation – inhibit humoral immunity
How do Tregs suppress immune cells?
Tregs use different mechanisms:
- deprive effector T cells of survival and growth factors (IL-2) via inhibitory cytokines
- direct killing of activated T cells (granzyme/Fas-dependent)
- inhibition of APCs (DCs, macrophages) via adenosine (via CD39, CD73 on Tregs)
- inhibition of APC activation via CTLA-4 on Tregs
Explain Tregs using inhibitory cytokines to suppress immune cells
Cytokines: TGF-B, IL-10 and IL-35
Production of these cytokines:
- inhibits differentiation, proliferation and activation of effector T cells
- suppress cytokine production by effector T cells
- TGF-b, IL-10, IL-35, promote conversion of activated conventional T cells into T cells with suppressive function (Treg)
TGF-B
- Inhibits effector T cells proliferation and function
- Blocks macrophage activation
- Promotes generation of iTreg from naïve CD4+ T cells (induces FoxP3 expression)
Other roles: Th-17-generation (combined with IL-6, IL-1, IL-23); tissue repair (collagen synthesis, angiogenesis); IgA switch in B cells
Interleukin-10 (IL-10)
- inhibits APC activation (DCs, MΦs)
- inhibits IL-12 production by DCs, MΦs
- inhibits co-stimulatory molecule expression on DCs, MΦs
o indirect inhibition of T cell activation
- promotes conventional T cell conversion into Tr1 regulatory cells
- Stimulates Galectin-1 to suppress growth and causes apoptosis of activated Th cells
IL-35
- block the development of Th1 and Th17 cells by limiting early T cell proliferation
- Seems to reduce the STAT1 signalling pathway
How do Treg use CD25 to suppress immune cells?
Expression of high levels of CD25 (IL-2R-alpha)
Treg cells suppress depletion of local IL-2. by acting as a sink for IL-2. Tregs therefore outcompetes effector T cells and therefore inhibits activation and proliferation (deprivation-mediated apoptosis)
IL-2 can then contribute to maintenance of Treg cells (CD4+CD25+ Treg)
How do Tregs use adenosine to inhibit APCs?
Tregs can express CD39/CD73 on their surface which can produce adenosine via ATP. Adenosine is immunosuppressive as it inhibits APC activation and maturation therefore inhibiting activation and responses from T cells. It also inhibits NK cells/
How do Tregs use cytolysis and diet killing to suppress cells?
Treg cells can either secrete granzymes and perforin for apoptosis
Or they can induce Fas on their cell surface which links with FasL on effector T cells to cause Fas-induced apoptosis
How do Tregs inhibit APC activation?
Treg cells can induce surface expression if CTLA-4, which decreases DC activity via costimulation.
CTLA-4 interacts with CD80/CD86 on DCs. This down-regulates CD80/CD86 to inhibit T cell activation by DCs
There is also induction of IDO (indoleamine 2,3-dioxygenase) expression on DCS. IDO catabolyses tryptophan into kynurenines = tryptophan starvation + high kynurenines. This inhibits proliferation; induce apoptosis of Tef
How do Tregs convert other immune cells into iTregs?
Induction of infectious tolerance. This promotes conversion of activated conventional T cells (Tconv) into cells with immunosuppressive properties (induced Tregs)
- TGF-β1 => converts convCD4+CD25- T cells into CD4+CD25+ Treg
- IL-10 => converts
conventional T cells into Tr1 cells (IL-10/TGF-β1) - IL-35 => converts conventional T cells into IL-35 expressing iTregs
