Trans-presentation of IL-15 modulates STAT5 activation and Bcl-6 expression in T(H)1 cells

During infection, naïve CD4(+) T helper cells differentiate into specialized effector subsets based upon environmental signals propagated by the cytokine milieu. Recently, this paradigm has been complicated by the demonstration that alterations in the cytokine environment can result in varying degrees of plasticity between effector T helper cell populations. Therefore, elucidation of the mechanisms by which cytokines regulate T helper cell differentiation decisions is increasingly important. The gamma common cytokine IL-15 is currently undergoing clinical trials for the treatment of malignancies, due to its well-established role in the regulation of natural killer and CD8(+) T cell immune responses. However, the effect of IL-15 signaling on CD4(+) T cell activity is incompletely understood. One mechanism by which IL-15 activity is conferred is through trans-presentation via the IL-15 receptor alpha subunit. Here, we demonstrate that differentiated T(H)1 cells are responsive to trans-presented IL-15. Importantly, while trans-presentation of IL-15 results in STAT5 activation and maintenance of the T(H)1 gene program, IL-15 treatment alone allows for increased Bcl-6 expression and the upregulation of a T(FH)-like profile. Collectively, these findings describe a novel role for IL-15 in the modulation of CD4(+) T cell responses and provide valuable insight for the use of IL-15 in immunotherapeutic approaches.