Lundbeckfonden - Unraveling the functional dichotomy of interleukin 2 and 15 signaling pathways

Interleukin-2 (IL-2) and IL-15 are pivotal cytokines that modulate the immune response by binding their receptors and initiating complex signaling cascades that culminate with the adequate gene expression regulation. Not surprisingly deregulation of these cytokines and/or their receptors is involved in several diseases including diverse leukemias. Hence, IL-2/IL-2R and IL-15/IL-15R systems are potential targets for immunotherapies. Indeed, IL-2 was accepted by the FDA for treating renal and melanoma cancer in the 90s. However, especially due to its role in inducing AICD, which results in self destruction of T-cells generated in response to the therapy, less damaging alternative therapies are required. In the present, IL-15 is one of the most promising candidates in cancer immunotherapy since it shares the beneficial effects of IL-2 without inducing such toxicity. The functional redundancy between IL-2 and IL-15 can be explained by the use of highly similar receptors given that both share two (IL2Rß and IL2Rg) out of the three subunits comprising their high affinity receptor complex. But at the same time, it remains a paradox how IL-2 and IL-15 can produce distinct responses using the same pair of signaling subunits. Aiming to shed light in that field, we performed the first large-scale quantitative phosphoproteomic study to dissect and compare the signaling cascades initiated by IL-2 and IL-15, finding that signaling properties of both cytokines are highly similar. However, an interesting combination of faint differences was detected, which in conjunction may be responsible for the functional dichotomy existing between the two closely-related interleukins. Hence, the aim of the proposed project is to characterize the regulatory changes in the signal transduction cascades initiated by IL-2 and IL-15, which could be beneficial for the development of specific immunotherapies based on the action of these two cytokines.