Abstract
Complex interactions between effector T cells and Foxp3+ regulatory T cells (Treg) contribute to clinical outcomes in cancer, and autoimmune and infectious diseases. Previous work showed that IL-12 reversed Treg-mediated suppression of CD4+Foxp3− T cell (Tconv) proliferation. We and others have also shown that Tregs express T-bet and IFN-γ at sites of Th1 inflammation and that IL-12 induces IFN-γ production by Tregs in vitro. To investigate whether loss of immunosuppression occurs when IFN-γ is expressed by Tregs we treated mouse lymphocyte cultures with IL-12. IFN-γ expression did not decrease the ability of Tregs to suppress Tconv proliferation. Rather, IL-12 treatment decreased Treg frequency and Foxp3 levels in Tregs. We further showed that IL-12 increased IL-2R expression on Tconv and CD8 T cells, diminished its expression on Tregs and decreased IL-2 production by Tconv and CD8 T cells. Together, these IL-12 mediated changes favored the outgrowth of non-Tregs. Additionally, we showed that treatment with a second cytokine, IL-27, decreased IL-2 expression without augmenting Tconv and CD8 T cell proliferation. Notably, IL-27 only slightly modified levels of IL-2R on non-Treg T cells. Together, these results show that IL-12 has multiple effects that modify the balance between Tregs and non-Tregs and support an important role for relative levels of IL-2R but not for IFN-γ expression in IL-12-mediated reversal of Treg immunosuppression.
Highlights
Natural regulatory T cells (Tregs), identified by the expression of Foxp3, play an important role in down-regulating immune responses and an imbalance between numbers of Tregs and conventional CD4 (Tconv) and CD8 T cells contributes to outcomes in cancer and autoimmune and infectious diseases [1,2,3,4]
IFN-c is expressed by virus-specific Tregs in the CNS of mice infected with the rJ2.2 strain of mouse hepatitis virus (MHV) [8]; we used information obtained from this experimental system as the basis for the approach described here
To determine whether cytokines had a role in IFN-c expression by Tregs, we initially focused on cytokines that are up-regulated in the CNS of MHV-infected mice and remain elevated as the infection resolves [15]
Summary
Natural regulatory T cells (Tregs), identified by the expression of Foxp, play an important role in down-regulating immune responses and an imbalance between numbers of Tregs and conventional CD4 (Tconv) and CD8 T cells contributes to outcomes in cancer and autoimmune and infectious diseases [1,2,3,4]. Interactions between Tregs and non-Tregs result in modifications of the function of both cell types, with the goal of minimizing detrimental side effects of pro-inflammatory immune responses while maximizing the efficacy of processes such as pathogen clearance. Unfractionated populations of Tregs harvested from inflammatory sites, which include cells expressing IFN-c, remain immunosuppressive. In a model of experimental autoimmune encephalomyelitis (EAE), CNS-derived epitope MOG35–55-specific Tregs showed reduced ability to inhibit proliferation of Tconv of the same specificity isolated from the inflamed CNS [9]. This reduction in inhibitory function was IL-6 and TNF-dependent
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