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Reply to ‘Comment on: Evidence of innate lymphoid cell redundancy in humans’

Nature Immunology volume 19, pages 789–790 (2018)Cite this article

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Vivier et al. reply: We thank Orange et al.1 for their interest in our study. Their remarks allow us the opportunity to clarify key aspects of NK cell biology that have been often overlooked. Our previous report analyzed the reconstitution of innate lymphoid cells (ILCs) in patients with severe combined immunodeficiency (SCID) who had received non-myeloablative hematopoietic stem cell transplantation (HSCT)2. We provided evidence showing that in conditions of modern medicine and hygiene, and when the functions of T cells and B cells are preserved, innate lymphoid cells (ILCs), including natural killer (NK) cells, seem to be dispensable for protective immunity. Orange et al. propose that human NK cells are “an essential, non-redundant component of the human immune system.”1 As discussed below, there are at least six pieces of information to be considered for assessment of the in vivo function of NK cells.

The analysis of primary immunodeficiencies is key for identification of the roles of cells and molecules in immunity. So far, and as described by Orange et al.1, there are seven reported inborn errors that lead to NK cell deficiencies (NKDs). The genes involved are GATA2, MCM4, GINS1, MCM10, IRF8, RTEL1 and FCGR3A. However, none of these genes are expressed exclusively in NK cells. More notably, although NKD is present in these patients, many cells of the immune system are affected. The consequences of the mutations are by no means restricted to NK cells. Thus, even if NK cells contribute to the clinical manifestations of the NKD, they are unlikely to be the only immune cells contributing to the disease. In deficiency in the transcription factor GATA2, all myeloid lineages are affected, as are B cells and T cells3. Deficiency in GINS1, MCM4 or MCM10 affects DNA replication; consequently, a defect in the gene encoding any of these molecules affects proliferative cells, as reported for neutrophils in GINS1-deficient patients4,5. T cell functions, which are heavily dependent on proliferation, could not be robustly tested in these three cases, which precludes the claim that these conditions could be considered pure NKDs. IRF8 is a major transcription factor for myeloid-cell differentiation, and IRF8 deficiency is associated with a deficiency in dendritic cells6. RTEL1 deficiency is a disease that results in abnormal telomeres, which affects NK cells, B cells, T cells and myeloid cells7. In deficiency in the immunoglobulin receptor FcγRIIIa (encoded by FCGR3A), NK cells are present but NK cell cytotoxicity is diminished, whereas antibody-dependent cell-mediated cytoxicity is, surprisingly, intact8. Furthermore, FCGR3A is also expressed by subsets of monocytes and macrophages. Thus, in the absence of convincing evidence of selective NKD in humans, it is impossible to draw unequivocal conclusions about the role of NK cells in immunity from the analysis of these clinical conditions.

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Authors and Affiliations

  1. Innate Pharma Research Labs, Innate Pharma, Marseille, France

    Eric Vivier

  2. Aix Marseille Université, CNRS, INSERM, CIML, Marseille, France

    Eric Vivier & Fréderic Vély

  3. APHM, Hôpital de la Timone, Service d’Immunologie, Marseille Immunopole, Marseille, France

    Eric Vivier & Fréderic Vély

  4. APHP, Hôpital Universitaire Necker-Enfants Malades, Centre de Référence Déficits Immunitaires Héréditaires, Paris, France

    Alain Fischer

  5. Université Paris Descartes–Sorbonne Paris Cité, Institut Imagine, Paris, France

    Alain Fischer

  6. INSERM, U1163, Paris, France

    Alain Fischer

  7. APHP, Hôpital Universitaire Necker-Enfants Malades, Unité d’Immunologie-Hématologie et Rhumatologie Pédiatrique, Paris, France

    Alain Fischer

  8. College de France, Paris, France

    Alain Fischer

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  1. Eric Vivier
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Correspondence to Eric Vivier or Alain Fischer.

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E.V. is an employee of Innate-Pharma.

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Vivier, E., Vély, F. & Fischer, A. Reply to ‘Comment on: Evidence of innate lymphoid cell redundancy in humans’. Nat Immunol 19, 789–790 (2018). https://doi.org/10.1038/s41590-018-0165-4

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