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

AIMS: 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. METHODS AND RESULTS: 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. CONCLUSION: 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.