IFN-γ: The Dr. Jekyll and Mr. Hyde of immunology?

IFNγ is a pleiotropic cytokine that plays a central role in the immune system. It is mostly produced by activated T and NK cells but its effects can be detected in most cell types. Although both pro- and anti-inflammatory properties have been ascribed to IFNγ in different settings, a manuscript by Cunnusamy and colleagues in this issue (1) exposes in the same study the dual antagonistic roles of IFNγ in seemingly similar corneal transplant models. IFNγ is well-known to be essential to establish Th1-type responses and is most commonly associated with their immunostimmulatory and pro-inflammatory effects (Figure 1). Indeed, IFNγ-mediated signaling induces or increases MHC expression on most cell types thereby facilitating antigen presentation, drives expression of co-stimulatory molecules on macrophages, recruits and activates lymphocytes and macrophages, increases the release of inflammatory mediators (2) and can antagonize the differentiation of inducible T regulatory cells (iTregs). Analysis of immune responses in IFNγ- or IFNγR-deficient mice, or in animals treated with IFNγ-neutralizing antibodies highlights its importance in promoting immune-mediated tumor rejection, resistance to pathogens and acute rejection of MHC class II-disparate skin and pancreatic islet allografts. Figure 1 Antagonistic consequences of IFNγ on immune responses. IFNγ-mediated signaling leads to recruitment and activation of lymphocytes and macrophages, release of inflammatory mediators such as reactive oxygen species and nitric oxide and increased ... However, in addition to the pro-inflammatory properties of IFNγ, additional studies have demonstrated another set of IFNγ attributes that highlight the dual personality of this cytokine (Figure 1). For instance, impairing IFNγ signaling prevented the induction of long-term skin and cardiac allograft survival by costimulation blockade therapies (3) and precipitated the rejection of corneal allografts (1). Thus, IFNγ can have a protective rather than detrimental effect on allografts. At least 2 mechanisms have been reported that may explain the inhibitory properties of IFNγ. First, IFNγ may promote the contraction phase of CD8+ T cells during a primary immune response, as has been described following Listeria infection, although this effect remains controversial (4). A second property of IFNγ that may play a role in the ability of IFNγ to contribute to the induction of transplantation tolerance is its capacity to induce expression and activation of the enzyme indoleamine 2,3-dioxygenase (IDO) in antigen presenting cells (APCs) and other cell types (5). IDO’s activity leads to the catabolism of the essential amino acid L-tryptophan and accumulation of its metabolites, including kynurenine. Tryptophan degradation results in reduced availability of this substrate both for pathogens (which contributes to the antimicrobial response), and for cellular consumption which results in reduced T cell proliferation. In addition, production of kynurenine can lead to T cell apoptosis and clonal deletion, effectively limiting antigen-specific T-cell responses. For instance, IDO is known to participate in maintaining maternal tolerance during pregnancy and in suppressing T-cell responses to major histocompatibility complex (MHC)-mismatched liver allografts and to self-antigens in a type I diabetes model. It is appealing to postulate that the net outcome of the apparent paradoxical effects triggered by IFNγ might be dictated by context-dependent triggers. For example, the abundance of pathogen-derived molecules in infectious models can be recognized by pattern-recognition receptors, and lead to activation of an IFNγ-induced pro-inflammatory response by innate immune cells. On the other hand, the tissue injury and/or neoangiogenesis that occur after solid organ transplantation may result in a local increase in tissue-repair molecules, such as TGFβ and chemotactic recruitment of monocytes. In this context, IFNγ produced by alloreactive NK and T cells may drive differentiation of such monocytes into immunosuppressive IDO-producing macrophages. The new findings reported by Cunnusamy and colleagues (1) highlight that IFNγ can have fundamentally opposite roles on the immune response in very similar experimental settings. Disrupting IFNγ signaling prevented generation of allospecific Tregs and precipitated the rejection of fully allogeneic corneal allografts when both MHC and minor histocompatibility (mHC) loci were mismatched (C57BL/6 into BALB/c), suggesting a predominantly immunosuppressive role for IFNγ in this context. However, when donors and recipients were mismatched only at MHC (but not mHC) or only at mHC (but not MHC) loci (BALB.B into BALB/c, or NZB into BALB/c), IFNγ-impairment promoted graft survival and enhanced antigen-specific Treg immunosuppressive activity, demonstrating the deleterious effect of IFNγ on these grafts. These dichotomous results on regulation and corneal graft outcome suggest that IFNγ signaling may have opposing consequences as a result of very subtle differences in the conditions that initiate the immune response, although the molecular mechanisms driving one pathway versus the other still need to be clarified. Can the seemingly paradoxical role of IFNγ in such only subtly different settings be explained by the recruitment of different innate immune cells, or the cooperation between a different set of cytokines? Is there a threshold in the number of antigen-specific T cell precursors beyond which IFNγ mediates immunosuppression instead of immunopotentiation? The answer to these and other pertinent questions should provide valuable insights into the benefits of IFNγ modulation in clinical setting and transplantation immunology in particular.