Regulation of CD4⁺CD25⁺ regulatory T cell activity: it takes (IL‐)two to tango

Abstract

Although CD4 + CD25 + regulatory T cells (Treg) represent a well-characterized population of T cells with in vitro and in vivo suppressive capacity, the basic mechanisms of suppression are still not understood. The constitutive expression of the high-affinity receptor for IL-2 has raised the question about the role of IL-2 in Treg function. Here, we review recent data indicating that IL-2 is not only necessary for the homeostasis of Treg but is also critical for the activation of Treg function. Since Treg do not produce IL-2 by themselves, their capacity to utilize IL-2 secreted by other T cells appears to be an essential component of Treg biology. This indicates that Treg suppressive activity is controlled by interaction with activated target cells via the soluble mediator IL-2. In Treg, IL-2 has been identified as a potent inducer of the immunosuppressive cytokine IL-10, an important mediator of Treg suppression in vivo. The efficient capture of IL-2 by Treg may, under conditions of limited IL-2 supply, cause IL-2 deprivation of responder T cells. This competition can explain some of the currently discussed discrepancies between in vivo and in vitro activity of Treg.

Human Cord Blood CD4+CD25hi Regulatory T Cells Suppress Prenatally Acquired T Cell Responses toPlasmodium falciparumAntigens

“…This is consistent with one possible mechanism of T regs suppression, in which high expression of CD25, or IL-2R, depletes cultures of IL-2 necessary for cell activation and growth, especially for Th1-type cells, whereas Th2-type cells can respond to other growth factors. This may occur under conditions that produce greater amounts of these additional growth factors (e.g., IL-4 and IL-9), such as during allergy season or in the fetal environment (66,69,70). This observation is consistent with our prior observations that newborns who develop a tolerant phenotype in utero show persistent suppression of malaria-specific Th1, but little suppression of malaria-specific Th2-type responses in childhood (22).…”

Aryl Hydrocarbon Receptor Activation Impairs the Priming but Not the Recall of Influenza Virus-Specific CD8+ T Cells in the Lung

“…T reg play an important role in the prevention of autoimmune disease and the regulation of immune responses to bacteria, tumors, and in GVH responses (63,64); however, the role of T reg in CD8 ϩ T cell responses during viral infection is less clear (65). Nevertheless, it was shown recently that in the context of a GVH response, AhR activation by TCDD stimulated a CD4 ϩ CD62L low CD25 ϩ subpopulation that expresses glucocorticoid-induced TNF receptor and CTLA-4, suggesting a role for T reg in TCDD-mediated suppression of CD8 ϩ T cell responses (66).…”

Is FOXP3 a bona fide marker for human regulatory T cells?

“…Although the molecular mechanism underlying this defective Th1 cytokine production remains to be determined, based on these data, it can be hypothesized that the lack of IL-2 by IPEX T cells could contribute to the faulty suppressive activity of nTreg cells. IL-2 is indeed required for the suppressive function of nTreg both in vitro and in vivo [25]. Interestingly, in vitro activation and expansion of IPEX nTreg in the presence of IL-2 restored their ability to suppress, with the exception of nTreg from IPEX patients carrying a mutation that abrogates protein expression [7].…”