Dissociated expression of IL-17, IL-22 and IFN-γ in naive CD4+ T lymphocytes

IL-17, IL-22 and IFN-γ are cytokines produced mostly by T helper (Th) cells playing different and essential roles in the defence against a wide variety of pathogens, but also responsible for tissue damages leading to several autoimmune diseases. Th cells producing IL-17 (Th17) and Th cells producing IFN-γ (Th1) belong to distinct subsets; however, Th17 cells producing IFN-γ are frequently found both in vivo and in vitro, leaving open the debate about the relative roles of Th17 and Th1 in autoimmune diseases. IL-22 is a cytokine playing pivotal roles in the repair and defence of epithelial, in the host defence against infections of extracellular pathogens and a protective role on hepatocytes damage during acute hepatitis. IL-22 is principally produced by Th17 cells, but a population of Th cells producing IL-22 in the absence of IL-17 and of IFN-γ has been described. To contribute to clarify the relationship among IL-17, IL-22 and IFN-γ and to identify factors relevant in induction of expression of these cytokines, we evaluated the pattern of expression of IL-17, IL-22 and IFN-γ in naive CD4+ T lymphocytes activated with anti-CD3 plus anti-CD28. Since the main factor determining the polarization of these cells is represented by cytokines produced by pathogen-activated APCs, we stimulated naive CD4+ T lymphocytes in the presence of a supernatant derived from IFN-γ-primed dendritic cells stimulated with zymosan (SNDCzym), which we previously demonstrated to efficiently induce IL-17 expression, or with a mixture of the cytokines IL-1β+IL-6+IL-23, analogously known for their capacity to polarize a Th17 response. Moreover, we used the SNDCzym with various combinations of antibodies neutralizing the cytokines IL-6, IL-12, IL-23 or with IL-1 receptor antagonist, inhibiting IL-1α and IL-1β, or with different mixtures of recombinant IL-1β, IL-6 and IL-23. The comparison of the results obtained from these two systems allowed us to clarify that the expression of IL-17, IL-22 and IFN-γ during naive CD4+ T lymphocyte differentiation is dissociated, depending on the combination of factors present in the cell environment. More relevantly, it allowed us to uncover that IL-6 and IL-23, commonly described in the mouse as inducers of IL-22 expression, both exert opposed roles, activatory or inhibitory, in IL-22 expression, depending on the context of factors in which they act.