Abstract
Interferon (IFN)-γ was originally characterized as a pro-inflammatory cytokine with T helper type 1-inducing activity, but subsequent work has demonstrated that mice deficient in IFN-γ or IFN-γ receptor show exacerbated inflammatory responses and accelerated allograft rejection, suggesting that IFN-γ also has important immunoregulatory functions. Here, we demonstrate that ex vivo IFN-γ conditioning of CD4 T cells driven by allogeneic immature dendritic cells (DC) results in the emergence of a Foxp3+ regulatory T-cell (Treg)- dominant population that can prevent allograft rejection. The development of this population involves conversion of non-Treg precursors, preferential induction of activation-induced cell death within the non-Treg population and suppression of Th2 and Th17 responses. The suppressive activity of IFN-γ is dependent on the transcription factor signal transducer and activator of transcription 1 and is mediated by induced nitric oxide. These data indicate not only how IFN-γ could be used to shape beneficial immune responses ex vivo for possible cell therapy but also provide some mechanistic insights that may be relevant to exacerbated inflammatory responses noted in several autoimmune and transplant models with IFN-γ deficiency.
Highlights
The role of interferon (IFN)-g in cellular immunity is somewhat paradoxical in that, it is usually considered to be a pro-inflammatory effector cytokine, increasing evidence suggests that it plays a non-redundant immunoregulatory role
The counter-regulation of Th2 and Th17 responses mediated by IFN-g, together with previous observations from this laboratory indicating that Treg generation in vivo is impaired in the absence of IFN-g [29], prompted us to ask whether this cytokine could be used to drive the emergence of alloreactive regulatory T cells ex vivo
The emergence of an increased proportion of Foxp31 regulatory cells in this system could be explained by apoptosis of responding non-Treg cells, expansion of endogenous Foxp31 cells, or conversion of non-Treg precursors since total CD41 cells from naive mice were used as the input population in these experiments
Summary
The role of interferon (IFN)-g in cellular immunity is somewhat paradoxical in that, it is usually considered to be a pro-inflammatory effector cytokine, increasing evidence suggests that it plays a non-redundant immunoregulatory role. Experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA) have been historically associated with IFN-g-producing Th1-dominant responses [1], but mice deficient in IFN-g or IFN-g receptor. A paradoxical role for IFN-g is seen in organ transplantation [9,10,11]. Allograft rejection is a process frequently associated with a dominant Th1 IFN-g response whereas the absence of.
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