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Regulatory T cells. Great opportunity to recognize every pathogenic antigen. Random generation of an immense T-cell repertoire (~ 10 15 different TCRs ):. BUT Potential self-reactivity. 5%. 95%. Control of potential T cell self-reactivity: tolerance. TOLERANCE: Central Peripheral.

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slide2

Great opportunity to recognize every pathogenic antigen

Random generation of an immense T-cell repertoire

(~1015 different TCRs):

BUT

Potential self-reactivity

5%

95%

Control of potential T cell self-reactivity: tolerance

  • TOLERANCE:
  • Central
  • Peripheral
slide3

T-cell INTRINSIC

T-cell ESTRINSIC

Clonal deletion

(apoptosis)

Regulatory T cells

Ignorance

Anergy

Tolerization mechanisms

slide4

Treg cells are essential for:

  • Maintaining peripheral tolerance (preventing autoimmunity)
  • Limiting chronic inflammatory diseases (immune homeostasis)

However, they:

  • Limit beneficial immunity
  • Limit antitumor immunity

Regulatory T cells

Regulatory T cells (Tregs) represent a population of T cells that are specialized for the suppression of the immune response;

slide5

Regulatory T cells: an old story…

Early 1970s: T cell-mediated suppression

however:

- lack of markers to distinguish suppressor T cells

  • difficulties in isolating suppressor T cells for further studies
  • lack of robustness of some suppressive phenomena
slide6

Regulatory T cells: re-discovered recently…

1995: S. Sakaguchi - Regulatory T cells

slide7

Regulatory T cells subsets

  • CD4+CD25+Foxp3+ Treg
  • Tr1
  • Th3
  • Other minor subsets (CD8+, CD4-CD8-,  T cells)
slide8

CD4+CD25+ Treg: origin

Tcell

Medium affinity

High

affinity

APC

Positive selection

Apoptosis/

Tregs

  • thymus-derived (Natural occurring Treg or nTreg)
  • induced in periphery ( CONVERSION)
slide10

CD4+CD25+ Tregs

- constitute 10% of circulating CD4+ pool in normal mice

- they are anergic

  • once activated, they do not produce IL-2
  • they proliferate less than effector T cells in vitro after ag stimulation, but in vivo they are continuosly proliferating due to self-ag recognition
  • they consume IL-2
  • they suppress effector function of other T cells
  • once activated in an ag-specific manner, their suppression is not limited to T cells with the same specificity
slide12

FoxP3 is induced in thymic precursor cells upon engagement with high-affinity TCR and other costimulatory factors resulting in FOXP3+ Treg cells. Different functions associated with Treg cell differentiation and function are shown in the boxes.

  • Generation of Treg in the thymus:
  • strong TCR engagement
  • signals to common -chain containing cytokyne receptors
  • CD28 costimulatory signals
slide14

CD25 (IL-2 receptor -chain)

  • transiently expressed in activated T cells;

constitutively expressed in Tcells with regulatory abilitites

  • at the steady state, 10% of peripheral CD4+ cells express CD25
slide15

CD25+ cell

depletion

Athimic Nude mouse

BALB/C mouse

CD4+ cells

CD4+CD25- cells

“…when CD4+ cell suspensions prepared from normal mice are depleted of

CD25+ cells and are then inoculated into athymic nude mice, all recipients spontaneously developed autoimmune disease…”

(S. Sakaguchi et al., 1995)

slide16

“…when CD4+ cell suspensions prepared from normal mice are depleted of CD25+ cells and are then inoculated into athymic nude mice, all recipients spontaneously developed autoimmune disease…”

(S. Sakaguchi et al., 1995)

slide17

Depletion of CD25+ cells is sufficient to eliminate T cells with regulatory activity (Treg)

Autoimmunity

“CD4+CD25+ cells contribute to maintaining self-tolerance by down-regulating immune response”

slide18

Foxp3 (Forkhead box P3)

  • forkhead/winged-helix transcription factor member
  • is located on the X chromosome
    • is exclusively expressed on Tregs (vs. CD25):
  • all the T cells which express high levels of Foxp3 are Treg
  • BUT
  • Foxp3 is not expressed in every Treg
slide20

Foxp3: IPEX and scurfy mice

  • IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked)
  • fatal autoimmune disease
  • rare
  • X-linked (as Foxp3 gene location!)
  • characterized by Foxp3 mutation and hyperresponsive CD4+ cells
slide22

Scurfy mice

The scurfy mutation can be rescued by a transgene encoding Foxp3 allele

slide23

Foxp3 in Treg development and function

Foxp3 KO mice have lower numbers of CD4+CD25+ cells

Conditional deletion of Foxp3in mature peripheral Tregs results in

- loss of suppressor function

- production of IL-2 and other pro-inflammatory cytokines

  • Expression of a Tg encoding Foxp3 convert naive T cells to Treg-like:
  • confers suppressor ability
  • CD25/CTLA4/GITR expression
  • repress IFN-IL-4/IL-2 production
slide26

Control of Treg function by Foxp3

Target genes

Foxp3 controls directly or indirectly nearly 700 genes

Foxp3 binds directly to nearly 10% of them

Among target genes:

  • signal transduction genes
  • transcription factors (!!!!!!!)
  • cytokines (e.g.Il2)
  • cell surace molecules
  • enzymes for cell metabolism
  • miRNA

Foxp3 functions as an activator as well as a repressor of the transcription depending on the target

slide27

CTLA-4 (Cytotoxic T lymphocyte antigen)

  • CD28-family receptor
  • It binds the same ligands as CD28 (CD80 and CD86)
  • higher affinity than CD28
  • T cell inibitory receptor CTLA4 KO die prematurely for multiorgan infalmmation

In nTregs:

  • Constitutively expressed (vs. transient expression in other T)
  • CTLA4 expression is controlled by Foxp3
  • required for their in vivo and in vitro suppression, (down-regulation of CD80 and CD86 on APC)
slide28

GITR (glucocorticoid-induced tumor necrosis factor receptor)

  • Expressed in activated T cells or in Tregs
  • role of GITR in attenuating the suppressive activity of CD4+ CD25+ T cells
slide32

Mechanisms of suppression: inhibitory cytokines

  • IL-35:
  • Recently discovered in mice
  • Not produced by human Tregs
  • TGF- and IL-10:
  • fundamental for iTreg mediated suppression
  • Their contribution to nTreg mediated suppression is debated
slide33

Mechanisms of suppression: cytotoxicity

Cell-contact dependent mechanism

slide34

Mechanisms of suppression: metabolic disruption

Cell-contact dependent mechanism (or close proximity)

Competition for cytokines (es IL-2 deprivation)

Delivery of a negative signal to Teff:

- upregulation of cAMPT cell proliferation and IL-2 production

- generation of pericellular adenosineT cell function

slide35

Mechanisms of suppression: functional modification of APC

Repression of APC function/ maturation:

-  CD80/CD86 expression via CTLA4

- indoleamine 2,3-dioxygenase (IDO) production

- LAG-3 dependent block of maturation

slide36

Relative contribution of different mechanisms of suppression

Hyp 1: operate synergistically and sequentially

Hyp 2: different mechanism for different scenario (contextual model)

Hyp 3: one/few critial and many accessory mechanism (hierarchical model)

slide38

Role of Treg in infectious disease

Infection activates both Tregs and effector function

Outcome of an infection

Effector response

Treg function

  • limit the magnitude of effector response (advantage/disadvantage for the host)
  • limit collateral tissue damage (advantage)
slide40

Role of Tregs in cancer

preventing autoimmunity

Treg suppress host immune response

Limit anti-tumor immunity

Ovarian tumors are infiltrated by both effector (CD4+CD25-) T cells and by an excess of TREG cells (CD4+CD25+). These TREG cells impede the function of the effectors in combating the tumor. The chemokine CCL22, produced by the tumor cells, binds to its receptor (CCR4) on the TREG cells and mediates their recruitment into the tumor.