Dissecting interferon-induced transcriptional programs in human peripheral blood cells.

Simon J Waddell,Michael Levin,Patrick O Brown,Kathleen H Rubins,David A Relman,Michael J Griffiths,Stephen J Popper,Derya Unutmaz

doi:10.1371/journal.pone.0009753

Abstract

Interferons are key modulators of the immune system, and are central to the control of many diseases. The response of immune cells to stimuli in complex populations is the product of direct and indirect effects, and of homotypic and heterotypic cell interactions. Dissecting the global transcriptional profiles of immune cell populations may provide insights into this regulatory interplay. The host transcriptional response may also be useful in discriminating between disease states, and in understanding pathophysiology. The transcriptional programs of cell populations in health therefore provide a paradigm for deconvoluting disease-associated gene expression profiles.We used human cDNA microarrays to (1) compare the gene expression programs in human peripheral blood mononuclear cells (PBMCs) elicited by 6 major mediators of the immune response: interferons α, β, ω and γ, IL12 and TNFα; and (2) characterize the transcriptional responses of purified immune cell populations (CD4+ and CD8+ T cells, B cells, NK cells and monocytes) to IFNγ stimulation. We defined a highly stereotyped response to type I interferons, while responses to IFNγ and IL12 were largely restricted to a subset of type I interferon-inducible genes. TNFα stimulation resulted in a distinct pattern of gene expression. Cell type-specific transcriptional programs were identified, highlighting the pronounced response of monocytes to IFNγ, and emergent properties associated with IFN-mediated activation of mixed cell populations. This information provides a detailed view of cellular activation by immune mediators, and contributes an interpretive framework for the definition of host immune responses in a variety of disease settings.

Highlights

Interferons are a class of cytokines first identified in 1957 as having a protective effect against viral infection [1]
peripheral blood mononuclear cells (PBMCs) cytokine activation profiles To investigate the temporal program of gene expression in a physiologically relevant mixed cell population specific to activators of innate immunity, we treated PBMCs with recombinant IFNa2b, IFNb1a, IFNv, IFNc, IL12 and TNFa and sampled at intervals of 0.5, 1, 4, 8, 12, and 24 h post stimulation
We characterized the differential effects of 6 cytokines on gene expression in a mixed population of human immune cells; defining for the first time the conserved transcriptional response to IFNv, together with IFNa and b, and revealing major similarities in IFNc and IL12 transcriptional programs

Summary

Introduction

Interferons are a class of cytokines first identified in 1957 as having a protective effect against viral infection [1]. The type I interferons, IFNa (of which there are 13 subtypes), IFNb and IFNv are secreted by most cell types in response to viral infection [5]. Mice lacking intact interferon receptors are highly susceptible to viral infection [6]. Type I interferon subtypes have been reported to have distinct activities [9,10]; these IFN subtype-specific effects are influenced by factors such as receptor binding efficiencies [11], constitutive levels of IFN expression [12], and the specific viral-target cell combination [13]. Interferons are involved in a wide range of clinically important phenomena, ranging from activation of immune responses to infection [14] to cancer suppression [16] to depression [17]. Recombinant interferon therapy has been approved for a spectrum of conditions such as hepatitis B and C infections, Kaposi’s sarcoma, multiple sclerosis and chronic granulomatous disease [5]

Methods

Results

Conclusion