Provided is an IL-15 heterodimeric protein, such as an IL-15/IL-15Rα heterodimeric protein. The IL-15 heterodimeric protein contains protein (I) and protein (II). Protein (I) is recombinantly produced by combining IL-15 or a variant thereof with a first Fc variant, and protein (II) is a second Fc variant, or recombinantly produced by combining IL-15Rα or a variant thereof with a second Fc variant. The first Fc variant and the second Fc variant are preferably linked via a “Knob-into-Hole” mode. Also provided are methods of using the IL-15 heterodimeric proteins to modulate an immune response. The provided IL-15 heterodimeric proteins have significant anti-tumor activity, better biological activity and prolonged in vivo half-life compared to the IL-15 molecule alone.