Interleukin-10 (IL-10), first recognized for its ability to inhibit activation and effector function of T cells, monocytes, and macrophages, is a multifunctional cytokine with diverse effects on most hemopoietic cell types. The principal routine function of IL-10 appears to be to limit and ultimately terminate inflammatory responses. In addition to these activities, IL-10 regulates growth and/or differentiation of B cells, NK cells, cytotoxic and helper T cells, mast cells, granulocytes, dendritic cells, keratinocytes, and endothelial cells. IL-10 plays a key role in differentiation and function of a newly appreciated type of T cell, the T regulatory cell, which may figure prominently in control of immune responses and tolerance in vivo. Uniquely among hemopoietic cytokines, IL-10 has closely related homologs in several virus genomes, which testify to its crucial role in regulating immune and inflammatory responses. This review highlights findings that have advanced our understanding of IL-10 and its receptor, as well as its in vivo function in health and disease.

Most, if not all, cells in humans and mice express the receptor for type I interferons (IFNs). Therefore, these cytokines have a range of direct and indirect effects on various cell types during infection with viruses, bacteria, parasites and fungi. Type I IFNs are important for host defence against viruses, through the induction of antiviral effector molecules that are encoded by IFN-stimulated genes. These IFNs can, however, cause immunopathology in acute viral infections. Conversely, they can lead to immunosuppression and loss of virus control during chronic viral infections. During bacterial infections, low levels of type I IFNs may be required early, to initiate cell-mediated immune responses. By contrast, type I IFNs have been shown to have adverse effects in infections with intracellular bacteria such as Listeria monocytogenes and Mycobacterium tuberculosis. In bacterial infections, high concentrations of type I IFNs may block B cell responses or may lead to the production of immunosuppressive molecules such as interleukin-10. Type I IFNs also antagonize the action of type II IFN (that is, IFNγ) by reducing the responsiveness of macrophages to activation by type II IFN. Another important antagonism is between type I IFNs and interleukin-1. This antagonism was recently shown to be important in M. tuberculosis infection and to be mediated by eicosanoids, in particular prostaglandin E2. Thus, type I IFNs are part of a complex cross-regulatory network, which leads mostly, but not always, to protection of the host against infectious diseases with minimum damage to the host.

Development of the appropriate CD4 ⁺ T helper (T _H ) subset during an immune response is important for disease resolution. With the use of naive, ovalbumin-specific αβ T cell receptor transgenic T cells, it was found that heat-killed Listeria monocytogenes induced T _H 1 development in vitro through macrophage production of interleukin-12 (IL-12). Moreover, inhibition of macrophage production of IL-12 may explain the ability of IL-10 to suppress T _H 1 development. Murine immune responses to L. monocytogenes in vivo are of the appropriate T _H 1 phenotype. Therefore, this regulatory pathway may have evolved to enable innate immune cells, through interactions with microbial pathogens, to direct development of specific immunity toward the appropriate T _H phenotype.

The immune response to Mycobacterium tuberculosis is complex and incompletely characterized, hindering the development of new diagnostics, treatments and vaccines. A systems-biology approach has now been used to compare the transcriptional profiles of expressed genes in patients with active and latent tuberculosis and in healthy controls. Active pulmonary disease is shown to correlate with a neutrophil-driven interferon-inducible gene profile. About 10% of people with latent tuberculosis go on to develop the active disease. In this study, 10% of latent patients displayed a transcriptional signature similar to that in the active disease, suggesting that the biomarker may be useful in both prognosis and diagnosis. Here, the human immune response to infection with Mycobacterium tuberculosis has been characterized by transcriptional profiling. The results show that active tuberculosis correlates with a particular transcriptional signature that is dominated by a neutrophil-driven interferon-inducible gene profile. The study provides a broad range of transcriptional biomarkers with potential as diagnostic and prognostic tools to combat the tuberculosis epidemic. Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis, is a major cause of morbidity and mortality worldwide. Efforts to control it are hampered by difficulties with diagnosis, prevention and treatment1,2. Most people infected with M. tuberculosis remain asymptomatic, termed latent TB, with a 10% lifetime risk of developing active TB disease. Current tests, however, cannot identify which individuals will develop disease3. The immune response to M. tuberculosis is complex and incompletely characterized, hindering development of new diagnostics, therapies and vaccines4,5. Here we identify a whole-blood 393 transcript signature for active TB in intermediate and high-burden settings, correlating with radiological extent of disease and reverting to that of healthy controls after treatment. A subset of patients with latent TB had signatures similar to those in patients with active TB. We also identify a specific 86-transcript signature that discriminates active TB from other inflammatory and infectious diseases. Modular and pathway analysis revealed that the TB signature was dominated by a neutrophil-driven interferon (IFN)-inducible gene profile, consisting of both IFN-γ and type I IFN-αβ signalling. Comparison with transcriptional signatures in purified cells and flow cytometric analysis suggest that this TB signature reflects changes in cellular composition and altered gene expression. Although an IFN-inducible signature was also observed in whole blood of patients with systemic lupus erythematosus (SLE), their complete modular signature differed from TB, with increased abundance of plasma cell transcripts. Our studies demonstrate a hitherto underappreciated role of type I IFN-αβ signalling in the pathogenesis of TB, which has implications for vaccine and therapeutic development. Our study also provides a broad range of transcriptional biomarkers with potential as diagnostic and prognostic tools to combat the TB epidemic.