Regulatory T cells

Regulatory T cells

1. Metabolic disruption

   • IL-2 deprevation
     • Due to high expression of CD25
     • suppress both IL-2 mRNA and protein production by Teff
   • cAMP
     • formed in Tregs and diffuses through gap junctions
       • Potent inhib 2nd messenger of Teff
   • Ectoenzymes - CD39 & CD73
     • Degrade ATP
       • ↑ adenosine (intra and extracellular)
         • A2A rec on Teff ∴ immunospression
           • ↑ iTreg via reduction of IL-6 and increase of TGFb
         • Promotes toleregenic phenotype of DC (Ernst)
           • Diagolo 2007
   • High expression HO-1
     • Heam degradation ∴ suppresive CO
       • byung Min 2005
         • HO-1 inhbits IL-2 production in Teff
         • HO-1 KO results in Th1 shift
     • induced by Foxp3
   • Galectin-10
     • Enter text here

2. Cytolysis

   • Granzyme A/B
     • Serine proteases cleave and activate caspases
       • apoptosis of Teff
       • Teff that over express the GB inhibitor SPI6 are resistant to Treg suppression (Noelle)
   • TRAIL-DR5 mediated apoptosis
   • Galectin-1 upreg in hu & mu Tregs

3. Dendritic Cells

   • ↓ maturation via LAG3
     • ITAM mediated inhib signalling via FcyRy. ERK mediated SHP1 recruitment
       • Silencing of signal transduction
         • ↓ Teff activation
     • CD4 homologue, bings w/ high aff to MHC II
       • Tregs may also express MHCII to bind with LAG3/CD4 on Teff in order to supress activation
         • Baecher Allen 2006
   • CTLA4
     • Interaction w/ CD80/86
       • IDO induction in DC
         • Degrades tryptophan
           • Essential for Tc growth and survival
           • Release of pro-apoptopic metabolites
       • Restricts CD28 binding
         • Co-stim required for Tc activation (w/ TCR)
           • Teff ligand sequestration
       • Endocysis of whole complex by Tregs
         • ↓ APC ligands ∴ stimulatory capacity
     • ↑ TGFb transcription
   • intravital microscopy shows direct interactions
   • neuropilin-1 - promotes prolonged DC/Treg interactions
     • preferncial binding of Tregs over Teff

4. Cytokines

   • IL-10
     • Signal for iTregs
   • TGFb
     • autocrine signalling for survival
     • Direct suppression of Teff
       • TGFb resistant Teff cannot be controlled by Tregs in IBD mouse models
     • Membrane tethered TGFb - controls CD8 infiltration to pancreatic ilets
       • Supresses Bc IgG production
       • Nakamura 2001
       • suppresed NK cells via NKG2D
     • soluable
   • IL-35
     • Heterodimeric protein preferentially expressed in Tregs
     • Collison 2007
   • IL-9
     • recruits & activates mast cells
       • essential regulatory mediators in allograft tolerance