Kindlin-3 sustains cytokine interleukin-2 signaling by linking its receptor to integrin LFA-1.

Kindlins are adaptor proteins that function synergistically with talin to activate integrins, facilitating cell adhesion and migration. In addition to this role, kindlins have other functions. In immune cells, kindlin-3 is the predominant kindlin paralog. Loss of kindlin-3 due to gene mutations leads to a bleeding disorder and impaired immune function, as observed in patients with leukocyte adhesion deficiency type III (LAD-III). In this study, we demonstrate that kindlin-3 maintains IL-2Rβ at the plasma membrane, a process that relies on the integrin LFA-1. This retention supports IL-2 signaling and helps protect natural killer (NK) cells from apoptosis when IL-2 levels are low. Kindlin-3 also promotes the colocalization of integrin LFA-1 and IL-2Rβ at sites where LFA-1 engages its ligand. Mechanistically, kindlin-3 directly binds the cytoplasmic domain of the interleukin-2 receptor β chain (IL-2Rβ) via its F0 subdomain. This interaction specifically targets a membrane-distal region of IL-2Rβ (residues 530-551) with micromolar affinity. Therefore, kindlin-3 acts as a bridging molecule that connects IL-2Rβ to the integrin LFA-1, thereby potentially coordinating cell adhesion with cytokine signaling.