Abstract
Mutations of the recombinase-activating genes 1 and 2 (RAG1 and RAG2) in humans are associated with a broad range of phenotypes. For patients with severe clinical presentation, hematopoietic stem cell transplantation (HSCT) represents the only curative treatment; however, high rates of graft failure and incomplete immune reconstitution have been observed, especially after unconditioned haploidentical transplantation. Studies in mice have shown that Rag−/− natural killer (NK) cells have a mature phenotype, reduced fitness, and increased cytotoxicity. We aimed to analyze NK cell phenotype and function in patients with mutations in RAG and in non-homologous end joining (NHEJ) genes. Here, we provide evidence that NK cells from these patients have an immature phenotype, with significant expansion of CD56bright CD16−/int CD57− cells, yet increased degranulation and high perforin content. Correlation was observed between in vitro recombinase activity of the mutant proteins, NK cell abnormalities, and in vivo clinical phenotype. Addition of serotherapy in the conditioning regimen, with the aim of depleting the autologous NK cell compartment, may be important to facilitate engraftment and immune reconstitution in patients with RAG and NHEJ defects treated by HSCT.
Highlights
Natural killer (NK) cells are effector and immunomodulatory cells of the innate immune system
We have demonstrated that NK cells from healthy infants comprise a higher proportion of CD56bright CD16−/int CD57− cells than what is observed in older healthy subjects, confirming previous observations [37,38,39]
It has been demonstrated that appearance of CD56bright cells precedes that of CD56dim cells after hematopoietic stem cell transplantation (HSCT) [40] and that it is possible to induce differentiation of CD56bright into CD56dim NK cells in vitro in response to signaling via fibroblast growth factor receptor 1 [41]
Summary
Natural killer (NK) cells are effector and immunomodulatory cells of the innate immune system. Through recognition of HLA class I molecules via activating and inhibitory killer cell immunoglobulin-like receptors (KIRs), and upon release of cytolytic granules, NK cells mediate killing of tumor and virus-infected cells and editing of dendritic cells, and play an important role in graft-versus-leukemia and graft rejection after hematopoietic stem cell transplantation (HSCT) [1,2,3,4]. They can modulate immune responses by secreting chemokines and cytokines [5, 6]. A subset of CD56low KIR+ NK cells, expressing CD57 represent terminally differentiated NK cells, whereas a further subset expressing the CD56− CD16+ CD57+ KIR+ phenotype are thought to represent exhausted NK cells [12]
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