Editorial: Protean effects of IL-10 include skin self-defense

Abstract

Discussion on how donor IL-10 production is essential for acceptance of syngeneic murine skin isografts.

In this issue of the Journal of Leukocyte Biology, Takiishi et al. [1] have detailed their relatively surprising discovery that donor IL-10 production was essential for the acceptance of syngeneic murine skin isografts. Keratinocytes, which have long been known to produce IL-10, particularly under certain conditions, such as UV irradiation [2], appeared to be the primary cellular source for the protective IL-10. As such, IL-10, which can protect against rejection when overexpressed in a solid organ allograft [3], also plays a role in syngeneic graft acceptance. The mechanism of allograft rejection is largely T cell-mediated, whereas the study by Takiishi et al. [1] indicates that the mechanism of syngeneic graft failure likely involves infiltration of “innate” cells into an area of surgical tissue injury. Specifically, the investigators found that infiltration of neutrophils into the syngeneic graft was curtailed by graft production of IL-10 (see Fig. 1A). Importantly, host IL-10 production was less important than isograft IL-10 production, indicating that high local cytokine concentrations in the isograft microenvironment were critical for graft protection. Further studies using host cells deficient in the IL-10R or IL-10R STAT3 signaling may further elucidate the biology of syngeneic graft failure and its modulation by IL-10.

Figure 1. An understanding of IL-10 biology has expanded greatly from an initial description as a “cytokine synthesis inhibitory factor”, which creates a Th1 → Th2 shift, to a protean regulatory molecule.

(A) Takiishi et al. [1] have found that IL-10-deficient murine skin isografts have an increased rate of graft failure; IL-10-mediated protection of isograft function is associated with an immediate down-regulation of graft infiltration by PMN cells. (B) In other research [4, 5], it has been demonstrated that antiviral or antitumor CD8⁺ T cells, which express a Th1/Tc1 phenotype, can coexpress IL-10 in later stages of T cell differentiation. Such Tc1 cell secretion of IL-10 can operate in an autocrine manner to actually increase expression of immune-protective molecules, such as IFN-γ and perforin and granzyme (P/Gz), thereby increasing target cell expression of MHCs; concomitantly, Tc1 cell IL-10 secretion serves to limit systemic inflammation and associated adjacent host tissue damage. Importantly, systemic administration of a long-acting formulation of PEG-IL-10 can mimic the effect of autocrine Tc1 cell IL-10 secretion.

The current results help extend the already protean role of IL-10, which was initially known simply as a cytokine synthesis inhibitory factor, which mediated Th2 cell regulation of Th1 cells [6]. Subsequently, a vast number of IL-10-mediated regulatory pathways have been described, which have relevance to human disease [7], including at the level of adaptive immunity (Th1/Th2 modulation) and innate immunity (in the Takiishi et al. report [1], modulation of neutrophil infiltration). The IL-10 story is becoming increasingly complex on several fronts. First, IL-10, which was initially considered a Th2-type cytokine, is now known to be transcribed off of a separate gene locus than the IL-4, IL-5, and IL-13 complex [8] and can be readily expressed in bone fide, T-bet transcription factor-expressing CD4⁺Th1 and CD8⁺Tc1 cells [9]. Such IL-10 production in Th1/Tc1 cells, at first glance, might be viewed as a mechanism for late-stage effector T cells to autoregulate, thus dampening immunity. However, new data in the literature indicate that such a view would be a dangerous oversimplification, as IL-10-producing T cells: (1) can improve host immunity by mediating antiviral effects, while simultaneously controlling adjacent host tissue injury [4] and (2) can mediate improved tumor cell killing by somewhat paradoxically allowing increased T cell expression of IFN-γ and cytolytic molecules, such as perforin and granzyme [5] (see Fig. 1B). This latter result, whereby IL-10 can actually increase IFN-γ expression, is somewhat at odds with the initial teaching of the Th1/Th2 paradigm (which emphasized IL-10/IFN-γ cross-regulation) but may help align the current skin isograft results in the context of previous studies, which found allograft IFN-γ content to be essential for graft acceptance [10]. On this point, it would be interesting to evaluate skin isografts deficient in IFN-γ or IL-10 for their susceptibility to graft failure.

Of note, a long-acting PEG-IL-10 can mimic the effects of T cell-derived IL-10 production for improved antitumor immunity [5]; in contrast, Takiishi et al. [1] were not able to consistently improve skin isograft acceptance in IL-10-deficient grafts through standard rIL-10 therapy. As such, it is likely that IL-10 may play an increasing role in novel immune therapies, provided that the strength of the cytokine signal can be optimized. In the Takiishi et al. [1] model, it would be interesting to determine whether increasing the IL-10 axis, through UV irradiation of the skin graft or by administration of a long-acting IL-10 molecule, might further improve isograft acceptance. It is possible that an ability to modulate IL-10 biology during skin isografting may have clinical implications, for example, in the setting of severe burn therapy [11].