Abstract
IL-6 plays a pivotal role in favoring T-cell commitment toward a Th17 cell rather than Treg-cell phenotype, as established through in vitro model systems. We predicted that in the absence of IL-6, mice infected with the gastrointestinal helminth Heligmosomoides polygyrus would show reduced Th17-cell responses, but also enhanced Treg-cell activity and consequently greater susceptibility. Surprisingly, worm expulsion was markedly potentiated in IL-6-deficient mice, with significantly stronger adaptive Th2 responses in both IL-6−/− mice and BALB/c recipients of neutralizing anti-IL-6 monoclonal Ab. Although IL-6-deficient mice showed lower steady-state Th17-cell levels, IL-6-independent Th17-cell responses occurred during in vivo infection. We excluded the Th17 response as a factor in protection, as Ab neutralization did not modify immunity to H. polygyrus infection in BALB/c mice. Resistance did correlate with significant changes to the associated Treg-cell phenotype however, as IL-6-deficient mice displayed reduced expression of Foxp3, Helios, and GATA-3, and enhanced production of cytokines within the Treg-cell population. Administration of an anti-IL-2:IL-2 complex boosted Treg-cell proportions in vivo, reduced adaptive Th2 responses to WT levels, and fully restored susceptibility to H. polygyrus in IL-6-deficient mice. Thus, in vivo, IL-6 limits the Th2 response, modifies the Treg-cell phenotype, and promotes host susceptibility following helminth infection.
Highlights
Interleukin-6 (IL-6) is a pleiotropic cytokine produced by multiple cell types and with wide-ranging functions and actions
In order to assess the contribution of IL-6 to chronic helminth immunity in a finely balanced Th2/the balance of regulatory and effector (Treg) setting, we first determined the survival of adult worms and the production of eggs as a measure of fitness over a 28-day period in IL-6-deficient and IL-6-sufficient BALB/c mice infected with H. polygyrus
After the first 14 days of infection, following emergence of the adult worm into the lumen, we found a significant reduction in egg burdens, a significant increase in intestinal granulomas as well as elevated Th2 responses in infected IL-6−/− mice (Fig. 1A and B and data not shown), adult worm burdens did not differ at this time point (Fig. 1C)
Summary
Interleukin-6 (IL-6) is a pleiotropic cytokine produced by multiple cell types and with wide-ranging functions and actions. Naıve T cells activated in the presence of IL-6 and TGF-β differentiate to Th17 cells to drive experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis, both of which are alleviated in IL-6−/− mice (reviewed in [9]). In the absence of IL-6, naıve T cells activated with IL-2 and TGF-β become Foxp3+ peripherally derived Treg (pTreg) cells [11]. The production of IL-6 from activated DCs has been shown to inhibit Treg-cell function [12], and expansion [13] or even induce thymus-derived Treg (tTreg) cells to become Th17 cells in the presence of TGF-β [14]. Our results revealed that IL-6 determines susceptibility to helminth infection by modifying the phenotype of the Treg-cell population and limiting protective Th2 responsiveness. Stimulation of Tregcell populations in the absence of IL-6 was crucial in regulating excessive pro-inflammatory responses and preventing resistance to helminth infection
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