Two studies have revealed a new role for WSX1 as a negative regulator of the cytokine response to intracellular pathogens.
Interleukin-27 (IL-27) signalling through its receptor (WSX1) has been shown previously to promote T helper 1 (TH1)-cell differentiation of naive CD4+ T cells. Surprisingly, two reports published in Immunity now indicate that WSX1 is also required for the suppression of cytokine responses.
TH1-type cytokines are crucial for resistance to intracellular pathogens. To determine the contribution of the IL-27–Wsx1 pathway to immunity, two groups have independently analysed Wsx1-deficient mice infected with intracellular pathogens, Trypanosoma cruzi and Toxoplasma gondii, respectively.
Hamano et al. observed that Wsx1-deficient mice were more susceptible to infection with T. cruzi than wild-type animals, showing increased mortality, prolonged parasitaemia and severe liver damage. Unexpectedly, although the percentage of splenocytes producing interferon- (IFN-) was no different in infected Wsx1-deficient and wild-type mice, the TH2-type cytokines IL-4 and IL-13 were highly overexpressed. By contrast, when liver mononuclear cells isolated from infected Wsx1-deficient mice were exposed to T. cruzi antigens in vitro, they produced markedly more IFN-, IL-6 and tumour-necrosis factor (TNF) than wild-type cells. IFN- was largely produced by CD4+ T cells and natural killer cells, whereas IL-6 and TNF were produced by both macrophages and T cells.
By treating Wsx1-deficient mice with either IL-4- or IFN--specific antibodies, skewing to the TH2 phenotype was shown to be responsible for the sustained parasitaemia, but not liver damage or increased mortality, both of which were dependent on IFN-. These results indicate that although regulation of the parasite burden and control of the immune response to prevent liver damage are independent processes, they both require Wsx1-mediated suppression of cytokine production.
In an independent study, Villarino et al. showed that Wsx1-deficient mice were more susceptible than wild-type animals to infection with T. gondii. Susceptibility was not a result of inefficient parasite clearance, but was due to CD4+ T-cell-mediated immune pathology. Although splenocytes isolated from infected Wsx1-deficient and wild-type animals produced similar levels of IFN- after in vitro stimulation at early time points post infection, at later times, Wsx1-deficient splenocytes produced markedly increased levels of the cytokine. This was a result of an increase in both the number of IFN--producing CD4+ T cells and the amount of cytokine they produced.
Interestingly, in in vitro culture systems, Wsx1 was required for optimal production of IFN- by naive CD4+ T cells stimulated under non-polarizing conditions, but under TH1-cell-polarizing conditions, naive CD4+ T cells from Wsx1-deficient mice produced greater amounts of IFN- than wild-type cells. Together with the observation that IL-27 induced the phosphorylation of STAT1 (signal transducer and activator of transcription 1), these results led the authors to suggest that WSX1 signalling is required for STAT1 activation, and subsequent TH1-cell differentiation, only when IL-12 is limiting, and that in situations in which IL-12 is plentiful — such as during T. gondii infection — WSX1 is not required for the generation of a TH1-cell response and is, in fact, required to prevent overproduction of cytokines.
Using Wsx1-deficient mice these two studies have revealed a new role for WSX1 as a negative regulator of the cytokine response to intracellular pathogens, making it a potential therapeutic target for the treatment of inflammatory diseases.
Karen Honey
References
Hamano, S. et al. WSX-1 is required for resistance to Trypanosoma cruzi infection by regulation of proinflammatory cytokine production. Immunity19, 657–667 (2003) | PubMed |
Villarino, A. et al. The IL-27R (WSX-1) is required to suppress T cell hyperactivity during infection. Immunity19, 645–655 (2003) | PubMed |
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