B2M triggers accelerated post-BMT immune reconstitution. (A) Anti-B2M antibody depletion reduced the immune rebuilding ability of alloreactive NK/DC coculture supernatants. (B) When B2M-KO H-2^b mice were lethally irradiated and given alloreactive NK cells and a T-cell–depleted BMT from WT H-2^d mice, no accelerated post-BMT immune reconstitution occurred. Also, no accelerated post-BMT immune reconstitution occurred when supernatants from cocultures of alloreactive WT H-2^d NK cells and B2M-KO DCs were infused in WT recipient mice. In contrast, infusion of supernatants from cocultures of alloreactive WT H-2^d NK cells and WT H-2^b DCs restored the B2M-KO mouse ability to undergo accelerated post-BMT immune reconstitution. (C) RNA sequencing (RNA-seq) volcano plot analysis displayed genes that were differentially expressed in the BM of mice 7 days after they had received TBI and infusion of alloreactive NK/DC coculture supernatants (without BMT rescue) vs infusion of nonalloreactive NK/DC coculture supernatants. RNA-seq analysis revealed significant upregulation of 2 master regulators of lymphocyte development, namely IL-7 and cKIT-L. (D) qPCR showed IL-7 and cKIT-L were stably upregulated (for 1 week) in the BM and thymus of lethally irradiated, alloreactive NK cell–treated mice. (E) Infusion of anti–IL-7 plus anti–cKIT-L antibodies into BMT-transplanted mice prevented accelerated immune reconstitution. ∗P < .05, ∗∗P < .01.