Innate immune recognition is critical for the induction of adaptive immune responses; however the underlying mechanisms remain incompletely understood. In this study, we demonstrate that T cell-specific deletion of the IL-6 receptor α chain (IL-6Rα) results in impaired Th1 and Th17 T cell responses in vivo, and a defect in Tfh function. Depletion of Tregs in these mice rescued the Th1 but not the Th17 response. Our data suggest that IL-6 signaling in effector T cells is required to overcome Treg-mediated suppression in vivo. We show that IL-6 cooperates with IL-1β to block the suppressive effect of Tregs on CD4+ T cells, at least in part by controlling their responsiveness to IL-2. In addition, although IL-6Rα-deficient T cells mount normal primary Th1 responses in the absence of Tregs, they fail to mature into functional memory cells, demonstrating a key role for IL-6 in CD4+ T cell memory formation.
The human body's ability to defend itself against pathogens relies on two distinct but connected systems: the innate and the adaptive immune systems. Innate immune cells survey their environment and use receptors located on their surface to distinguish between molecules that are harmless and molecules that stem from pathogens. When the cells of the innate immune system detect a pathogen, they secrete signaling molecules to alert adaptive immune cells to the invaders. Both sets of immune cells then mount a coordinated attack that usually kills the pathogen.
The adaptive immune system also produces memory cells that retain information about the pathogen: this allows the organism to mount a fast and efficient immune response the next time the same type of pathogen strikes. However, it is not completely understood how the innate immune system communicates with the adaptive immune system to allow these processes to take place.
One of the signaling molecules involved in the communication between different types of immune cells is a protein called Interleukin 6 (IL-6). This protein must be produced in order to trigger the immune response: however, many immune cells are able to recognize and respond to IL-6, so it has been difficult to study its impact on specific cell types.
Nish et al. have now investigated the effects of IL-6 on T cells, one of the main types of adaptive immune cell, by creating mice with T cells that are not able to recognize IL-6. The detection of pathogens by innate immune cells normally has several effects: the population of T cells increases; the T cells produce daughter cells—T helper cells—that support innate immune cells in killing pathogens; and memory cells are formed. Nish et al. find that these responses are impaired in the mutant mice.
To understand why, Nish et al. turn to T regulatory cells; these are adaptive immune cells that control the strength of the immune response. These experiments show that when T cells are ‘blind’ to IL-6, they are more sensitive to the action of T regulatory cells, and this disturbs the delicate balance between the stimulation and inhibition of the immune system. Nish et al. go on to show that IL-6 works together with another signaling molecule, Interleukin 1, to regulate how the T cells respond. The work helps to explain how the adaptive immune system mounts an immune response against pathogens but not against the host's own tissues.