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Regulatory T cells

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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Regulatory T cells

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  1. Regulatory T cells

  2. 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

  3. T-cell INTRINSIC T-cell ESTRINSIC Clonal deletion (apoptosis) Regulatory T cells Ignorance Anergy Tolerization mechanisms

  4. 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;

  5. 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

  6. Regulatory T cells: re-discovered recently… 1995: S. Sakaguchi - Regulatory T cells

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

  8. 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)

  9. % Foxp3

  10. 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

  11. CD4+CD25+Foxp3+ Treg generation in the thymus

  12. 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

  13. CD4+CD25+ Treg: markers

  14. 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

  15. 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)

  16. “…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)

  17. 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”

  18. 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

  19. its function is fundamental in Treg differentiation

  20. 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

  21. Scurfy mice The scurfy mutation can be rescued by a transgene encoding Foxp3 allele

  22. 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

  23. Control of Treg function by Foxp3 Interaction with TFs

  24. 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

  25. 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)

  26. 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

  27. IL-2 and Tregs

  28. Mechanisms of suppression

  29. 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

  30. Mechanisms of suppression: cytotoxicity Cell-contact dependent mechanism

  31. 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

  32. 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

  33. 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)

  34. Induced or adaptive regulatory T cells (iTregs) • Foxp3+ iTregs • Tr1 • Th3

  35. 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)

  36. Nature Immunology 6, 353 - 360 (2005)

  37. 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.

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