Regulatory T cells (T-regs) play a critical role in suppressing anti-tumor T-cells, helping tumors evade immune responses. Researchers now have revealed that the IL-2 receptor (IL-2R) found at the surface of T-regs has a dual role in preventing effector T-cells from functioning.
The study, “An essential role for the IL-2 receptor in Treg cell function“, published in Nature Immunology“, may have important implications for the development of novel immunotherapies that target the function of T-regs.
T-regs are key players in tumor immune evasion. They suppress the activity of effector T-cells, such as cytotoxic T-cells, which recognize and kill tumor cells, and helper T-cells, which have an anti-tumor role but also participate in other immune responses.
Previous work from this group and others had demonstrated that IL-2R is required for the generation and maintenance of T-regs. But so far, researchers had not been able to address the importance of IL-2R in mature T-regs. Deleting IL-2R genes in mice failed to answer this question because eliminating IL-2R results in a lethal ability to generate T-regs.
To overcome this problem, the researchers developed mice lacking the IL-2R genes only in their T-regs. This allowed them to identify two distinct ways through which IL-2R participates in effector T-cell suppression.
Results showed that although IL-2R-mediated signaling was required and sufficient for suppression of helper T-cells, the IL-2 receptor itself was sufficient to suppress cytotoxic T-cells without the need for IL-2R signaling activation.
“We found that it’s not only signaling through the IL-2 receptor that’s required for their control of cytotoxic T cells, but also the receptor’s ability to capture IL-2 and deprive cytotoxic T cells of access to this interleukin, which these cells need as well,” Alexander Rudensky, director of the Ludwig Center at Memorial Sloan Kettering in New York, said in a press release.
Since altered intestinal immune responses have been linked to the promotion of gastrointestinal (GI) cancer, researchers sought to examine how IL-2R signaling in T-regs participated in the development of the disease in mice that are prone to develop the disease in their small intestine.
“Our findings suggest that regulatory T cells have a dual role in inflammation-associated GI cancers, limiting precancerous lesions in the early stages, but promoting cancerous growths in later stages of the disease,” said Rudensky.
Understanding how T-regs can be manipulated to prevent GI cancer is one of the goals of a $10 million program launched by Ludwig and the Conrad N. Hilton Foundation, which is focused on the prevention of GI malignancies through dietary interventions.
But these findings also can have important implications for cancer immunotherapies. Since cytotoxic T-cells are activated by IL-2, “one way of releasing them from T-reg-mediated suppression would be to provide them with interleukin 2 in a targeted manner,” said Rudensky.
In autoimmune and inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease, and type 2 diabetes, this targeted delivery of IL-2 could be used to activate T-regs alone. In future approaches, Rudensky and his team hope to examine whether such targeted activation can be achieved.
