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Abstract
The physiological function of the immune system and the response to therapeutic immunomodulators may be sensitive to combinatorial cytokine micro-environments that shape the responses of specific immune cells. Previous work shows that paracrine cytokines released by virus-infected human dendritic cells (DC) can dictate the maturation state of naïve DCs. To understand the effects of paracrine signaling, we systematically studied the effects of combinations cytokines in this complex mixture in generating an anti-viral state. After naïve DCs were exposed to either IFNβ or to paracrine signaling released by DCs infected by Newcastle disease virus (NDV), microarray analysis revealed a large number of genes that were differently regulated by the DC-secreted paracrine signaling. In order to identify the cytokine mechanisms involved, we identified 20 cytokines secreted by NDV infected DCs for which the corresponding receptor gene is expressed in naïve DCs. By exposing cells to all combinations of 19 cytokines (leave-one-out studies), we identified five cytokines (IFNβ, TNFα, IL-1β, TNFSF15, and IL28) as candidates for regulating DC maturation markers. Subsequent experiments identified IFNβ, TNFα, and IL1β as the major contributors to this anti-viral state. This finding was supported by infection studies in vitro, by T-cell activation studies and by in vivo infection studies in mouse. Combination of cytokines can cause response states in DCs that differ from those achieved by the individual cytokines alone. These results suggest that the cytokine microenvironment may act via a combinatorial code to direct the response state of specific immune cells. Further elucidation of this code may provide insight into responses to infection and neoplasia as well as guide the development of combinatorial cytokine immunomodulation for infectious, autoimmune, and immunosurveillance-related diseases.
Highlights
The limitations of single cytokine therapy have motivated interest in evaluating the effects of combinatorial treatment
To compare the effects of paracrine signaling to the effects of a single cytokine treatment, we exposed naive dendritic cells (DC) either to paracrine signaling from Newcastle disease virus (NDV) infected cells or to IFNβ at a concentration found in the supernatants of NDV infected DCs
The Principal component analysis (PCA) showed that cells exposed to paracrine signaling from infected DCs had a different overall expression profile than cells exposed to IFNβ alone (Figure 1A)
Summary
The limitations of single cytokine therapy have motivated interest in evaluating the effects of combinatorial treatment. IFNα, which is the current therapy for chronic hepatitis C infection, fails to clear HCV titers in half of treated patients [1]. The cytokine interferon beta (IFNβ) has limited activity against multiple sclerosis in a large segment of patients [2]. Cytokine combination therapy, where two or more cytokine-based medications are simultaneous administered to treat a single disease, has shown promise in multiple medical conditions, such as cancer [3], myocardial infarction [4], and osteoporosis [5]. Recent studies have begun to reveal how combined extracellular stimuli can synergistically direct the responses of immune cells. Despite its potential, studying combinations of cytokines is experimentally difficult and relatively little systematic exploration in this important area has been reported
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