Table I.

Mechanisms proposed to influence suppression mediated by CD4+ CD25+ T cellsa

Suppressive MechanismProposed ActionSupporting EvidenceContradictory EvidenceRefs.
CTLA-4Binding to B7.1/B7.2; induction of IDO in DCCTLA-4 knockout mouse exhibits polyautoimmune phenotypeTreg retain suppressive action in APC free cultures 51 53 66
LAG-3 (CD223)UnknownBlocking Abs abrogate suppression in vitro and in vivoLack of overt autoimmunity in LAG-3 knockout mouse 67 68 69
GITRProvides T cell costimulatory signal; induces IL-10 productionmAb blockade of GITR in mice abrogates suppression in vitro and in vivoGITR is also expressed on activated effector cells and blockade may render resistant to suppression by Treg 70 71 72
IL-2R affinityOutcompete IL-2 from Teff cellsNeutralization of IL-2 mimics Treg action; addition abrogates suppression mediated by TregStoichiometry of suppression and Treg activation requirements suggests active mechanism 73 74
Soluble mediators
 TGF-βMembrane-bound active form exerts suppressive functionsHigh concentrations of polyclonal Ab abrogate suppressionTranswell experiments, neutralizing Abs, and cytokine knockout mice raise questions about direct effects 18 21 75
 IL-10Activation of Th1 reactive cells is controlledInjection of blocking Ab in vivo abrogates protection in an IBD modelProtective functions of CD4+ CD25+ fraction are independent of IL-10 76 77
  • a GITR, Glucocorticoid-induced TNFR-regulated gene; IBD, inflammatory bowel disease.