Cells exist within complex milieus of communicating factors, such as cytokines, that combine to generate context-specific responses, yet nearly all knowledge about the function of each cytokine and the signaling propagated downstream of their recognition is based on the response to individual cytokines. Here, we found that regulatory T cells (Tregs) integrate concurrent signaling initiated by IL-2 and IL-4 to generate a response divergent from the sum of the two pathways in isolation. IL-4 stimulation of STAT6 phosphorylation was blocked by IL-2, while IL-2 and IL-4 synergized to enhance STAT5 phosphorylation, IL-10 production, and the selective proliferation of IL-10-producing Tregs, leading to increased inhibition of conventional T cell activation and the reversal of asthma and multiple sclerosis in mice. These data define a mechanism of combinatorial cytokine signaling and lay the foundation upon which to better understand the origins of cytokine pleiotropy while informing improved the clinical use of cytokines.

Innate lymphoid cells (ILCs) represent the most recently identified subset of effector lymphocytes, with key roles in the orchestration of early immune responses. Despite their established involvement in the pathogenesis of many inflammatory disorders, the role of ILCs in cancer remains poorly defined. Here we assessed whether human ILCs can actively interact with the endothelium to promote tumor growth control, favoring immune cell adhesion. We show that, among all ILC subsets, ILCPs elicited the strongest upregulation of adhesion molecules in endothelial cells (ECs) in vitro, mainly in a contact-dependent manner through the tumor necrosis factor receptor- and RANK-dependent engagement of the NF-κB pathway. Moreover, the ILCP-mediated activation of the ECs resulted to be functional by fostering the adhesion of other innate and adaptive immune cells. Interestingly, pre-exposure of ILCPs to human tumor cell lines strongly impaired this capacity. Hence, the ILCP–EC interaction might represent an attractive target to regulate the immune cell trafficking to tumor sites and, therefore, the establishment of an anti-tumor immune response.