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Allogeneic hematopoietic transplantation is a powerful treatment for hematologic malignancies. Post-transplant immune incompetence exposes patients to disease relapse and infections. We previously demostrated that donor alloreactive natural killer (NK) cells ablate recipient hematopoietic targets, including leukemia. Here, in murine models, we show that infusion of donor alloreactive NK-cells triggers recipient dendritic cells (DCs) to synthesize beta-2-microglobulin (B2M) that elicits the release of c-KIT-Ligand and interleukin-7 that greatly accelerate post-transplant immune reconstitution. An identical chain of events was reproduced by infusing supernatants of alloreactive NK/DC co-cultures. Similarly, human alloreactive NK-cells triggered human DCs to synthesize B2M that induced interleukin-7 production by thymic epithelial cells and thereby supported thymocyte cellularity in vitro. Chromatography fractionation of murine and human alloreactive NK/DC co-culture supernatants identified a protein with molecular weight and isoelectric point of B2M and mass spectrometry identified amino-acid sequences specific of B2M. Anti-B2M antibody depletion of NK/DC co-culture supernatants abrogated their immune rebuilding effect. B2M knock-out mice were unable to undergo accelerated immune reconstitution but infusion of (wild type) NK/DC coculture supernatants restored their ability to undergo accelerated immune reconstitution. Similarly, silencing the B2M gene in human DCs, before co-culture with alloreactive NK cells, prevented the increase in thymocyte cellularity in vitro. Finally, human recombinant B2M increased thymocyte cellularity in a TEC/thymocyte culture system. Our studies uncover a novel therapeutic principle for treating post-transplant immune incompetence and suggest that, upon its translation to the clinic, patients may benefit from adoptive transfer of large numbers of cytokine-activated, ex-vivo expanded donor alloreactive NK-cells.

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