Natural killer cell crosstalk with allogeneic human cardiac-derived stem/progenitor cells controls persistence

Allogeneic human cardiac-derived stem/progenitor cells (hCPC) are promising candidates for cardiac repair. They interact with T cells, major effectors of the adaptive immune response, inducing 'paracrine' anti-inflammatory effects that could sustain tissue repair/regeneration. Natural killer (NK) cells are major effectors of the innate immune system that might influence the persistence of therapeutic stem/progenitor cells. Therefore, to get through successful clinical translation and anticipate allogeneic hCPC persistence, we defined their crosstalk with NK cells under steady state and inflammatory conditions. By using an experimental model of allogeneic hCPC/NK cell interaction, we demonstrate that hCPC moderately trigger cytokine-activated, but not resting, NK cell killing that occurs through formation of lytic immunological synapse and NK cell natural cytotoxicity. Yet, inflammatory context substantially decreases their capacity to set cytokine-activated NK cell functions towards NK cell-cytotoxicity and protects hCPC from NK cell killing. Allogeneic hCPC also restrain NK cell-cytotoxicity against conventional targets and inflammatory cytokine secretion biasing the latter towards anti-inflammatory cytokines. Thus, hCPC are unprivileged targets for allogeneic NK cells and can restrain NK cell functions in allogeneic setting. Collectively, our data suggest that allogeneic hCPC/innate NK cells crosstalk within injured inflamed myocardium would permit their retention and might contribute to attenuating inflammation and to preventing adverse cardiac remodelling.