CD25+CD4+ T cells compete with naive CD4+ T cells for IL-2 and exploit it for the induction of IL-10 production

Abstract

Maintenance of homeostasis in the immune system involves competition for resources between T lymphocytes, which avoids the development of immune pathology seen in lymphopenic mice. CD25+ CD4+ T cells are important for homeostasis, but there is as yet no consensus on their mechanisms of action. Although CD25+ CD4+ T cells cause substantial down-regulation of IL-2 mRNA in responder T cells in an in vitro co-culture system, the presence of IL-protein can be demonstrated by intracellular staining. As a consequence of competition for IL-2, CD25+ CD4+ T cells further up-regulate the IL-2R alpha chain (CD25), a process that is strictly dependent on IL-2, whereas responder T cells fail to up-regulate CD25. Similarly, adoptive transfer into lymphopenic mice showed that CD25+ CD4+ T cells interfere with CD25 up-regulation on co-transferred naive T cells, while increasing their own CD25 levels. IL-2 sequestration by CD25+ CD4+ T cells is not a passive phenomenon but instead initiates--in conjunction with signals through the TCR--their differentiation to IL-10 production. Although IL-10 is not required for in vitro suppression, it is vital for the in vivo function of regulatory T cells. Our data provide a link explaining the apparent difference in regulatory mechanisms in vitro and in vivo.

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

“…Thus, Treg competition for IL-2 is boosted by the positive-feedback loop of IL-2 uptake and CD25 up-regulation. The same inverse regulation of CD25 expression on Treg versus responder T cells has been observed in vivo [12,17] upon adoptive co-transfer of Treg and responder T cells.…”

“…In line with these indirect data, de la Rosa et al [15] and others [17] showed that IL-2 is critical for priming Treg for IL-10 production. Preliminary data from our laboratory also indicate that IL-2 is required in vivo to prime Treg for IL-10 production (A. Scheffold, unpublished observations).…”

“…The constitutive expression of all three chains of the high-affinity IL-2 receptor enables Treg to take up IL-2 without previous activation [15,26]. Using the CD25 expression level, which is positively regulated by IL-2 [32,33], as an indicator for IL-2 uptake, it has been demonstrated in vitro and in vivo that competition for IL-2 indeed occurs [12,15,17]. During co-culture of Treg with responder T cells, Treg up-regulate CD25, whereas induction of CD25 expression on responder T cells is suppressed.…”

“…Recent data indicate that IL-2 is critical for the activation of Treg effector function, such as production of IL-10. Since Treg do not produce IL-2 they seem to depend on their capacity to efficiently compete for IL-2 with their target T cells -activated dendritic cells or conventional T cells [5,[13][14][15][16][17].…”

CD25 Shedding by Human Natural Occurring CD4+CD25+ Regulatory T Cells does not Inhibit the Action of IL‐2

“…Alternatively, HT-2 cells could be less sensitive to IL-2 deprivation then classical CD4 + T cells. In contrast, murine CD4 + CD25 + T cells have been shown in part to mediate their action through competition for IL-2 by binding to membrane bound CD25 [14].…”