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Evidence of innate lymphoid cell redundancy in humans

A Corrigendum to this article was published on 16 November 2016

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Innate lymphoid cells (ILCs) have potent immunological functions in experimental conditions in mice, but their contributions to immunity in natural conditions in humans have remained unclear. We investigated the presence of ILCs in a cohort of patients with severe combined immunodeficiency (SCID). All ILC subsets were absent in patients with SCID who had mutation of the gene encoding the common γ-chain cytokine receptor subunit IL-2Rγ or the gene encoding the tyrosine kinase JAK3. T cell reconstitution was observed in patients with SCID after hematopoietic stem cell transplantation (HSCT), but the patients still had considerably fewer ILCs in the absence of myeloablation than did healthy control subjects, with the exception of rare cases of reconstitution of the ILC1 subset of ILCs. Notably, the ILC deficiencies observed were not associated with any particular susceptibility to disease, with follow-up extending from 7 years to 39 years after HSCT. We thus report here selective ILC deficiency in humans and show that ILCs might be dispensable in natural conditions, if T cells are present and B cell function is preserved.

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Figure 1: Normal abundance of ILCs in the peripheral blood of healthy pediatric and adult subjects.
Figure 2: Severe ILC lymphopenia in patients with SCID who have mutation of JAK3.
Figure 3: Long-term ILC lymphopenia in HSCT-treated patients with SCID.
Figure 4: Intestinal and skin ILCs in HSCT-treated patients with SCID.
Figure 5: Reconstitution of ILCs after engraftment of adult multipotent progenitor cells into Rag2−/−Il2rg−/− mice.

Change history

  • 19 October 2016

    In the version of this article initially published, author Mikael Ebbo was missing from the author list. The correct list is as follows: Frédéric Vély1,2,20, Vincent Barlogis3,20, Blandine Vallentin3,20, Bénédicte Neven4–7,20, Christelle Piperoglou1,2, Mikael Ebbo1,8, Thibaut Perchet9,10, Maxime Petit9,10, Nadia Yessaad11, Fabien Touzot5,12, Julie Bruneau5,13, Nizar Mahlaoui4–7, Nicolas Zucchini14, Catherine Farnarier2, Gérard Michel3, Despina Moshous4–7, Stéphane Blanche4–7, Arnaud Dujardin15, Hergen Spits16, Jörg H W Distler17, Andreas Ramming17, Capucine Picard4–7,18, Rachel Golub9,10, Alain Fischer4–7,19,21 & Eric Vivier1,2,21. The correct affiliation list ends as follows: 8APHM, Hôpital de la Timone, Service de Médecine Interne, Marseille, France. 9Institut Pasteur, Unité de Lymphopoièse, INSERM, Paris, France. 10Université Paris Diderot, Sorbonne Paris Cité, Cellule Pasteur, Paris, France. 11MI-mAbs consortium, Aix-Marseille University, Marseille, France. 12APHP, Hôpital Necker-Enfants Malades, Biotherapy Unit, Paris, France. 13APHP, Hôpital Necker-Enfants Malades, Service d'anatomopathologie, Paris, France. 14BD Biosciences, Le Pont-de-Claix, France. 15Innate-Pharma, Marseille, France. 16Academic Medical Center at the University of Amsterdam, Arizona Amsterdam, the Netherlands. 17Department of Internal Medicine, Rheumatology & Immunology, University of Erlangen-Nuremberg, Erlangen, Germany. 18APHP, Hôpital Necker-Enfants Malades, Study Center of Immunodeficiencies, Paris, France. 19College de France, Paris, France. 20These authors contributed equally to this work. 21These authors jointly directed this work. The correct Author Contributions section ends as follows: "...and M.E., N.M., N.Z., C.F., G. M., D.M., S.B., A.D., H.S. and C. Pic. provided key expertise, reagents or samples." In addition, the description of patient C9 was incorrect in the text and legend for Figure 4b,d. The correct text (in the final paragraph of the fourth subsection of Results) is as follows: "In addition, NKp46+ ILCs and ILC2s were readily observed in tissues from patients treated with myeloablative HSCT, as illustrated by the analysis of skin biopsies from a patient with SCID who had mutation of RAG2 (C10) and was treated with myeloablative HSCT (Fig. 4b,d).... As a control, tissue-resident gut ILCs were observed in a patient with SCID who had mutation of RAG1 (C9) but was treated with 'pheno-related' HSCT (related donor with more than one compatible HLA haplotype but not genetically identical) under non-myeloablative conditions (Fig. 4b,d). The correct Figure 4b,d legend is as follows: "(b) Microscopy of tissue sections from patients who were treated with HSCT (stained as in a): duodenum (left) or colon (right) from C9 (RAG1 mutation) and skin from C10 (RAG2 mutation) (middle), at 15 months (C9) or 4 months (C10) after HSCT....(d) Microscopy of tissue sections from patients with SCID (colon from P5 and skin from P11 (as in a); colon from C9 and skin from C10 (as in b))...." Also, a label was missing under Figure 1d, far left; that should be labelled as 'LinCD127+'. Finally, the description of lung NK cells in the final paragraph of Results was incorrect; that text should read as follows: "Similarly, lung NK cells (LinNKp46+NK1.1+CD127) underwent reconstitution...." These errors have been corrected in the PDF and HTML versions of this article.


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We thank all patients and their families for participating in the study; C. Bonnafous and N. Anceriz (Innate-Pharma) for monoclonal antibody to NKp46; F. Suarez (Paris), N. Schleinitz (Marseille) and Y. Bertrand (Lyon) for enrolling patients in the study; and the Laboratory of Hematology (P.E. Morange, Marseille) for sample storage. Supported by the European Research Council (THINK Advanced Grant for the E.V. laboratory), the Ligue Nationale contre le Cancer (Equipe Labellisée; E.V. laboratory), institutional grants from INSERM, CNRS and Aix-Marseille University to CIML (E.V. laboratory), the Institut Universitaire de France (E.V.), the European Research Council (Pidimmune Advanced Grant for the A.F. laboratory), institutional grants from INSERM, Paris Descartes University and Collège de France (A.F. laboratory), Investissements d'Avenir Instituts Hospitaliers Universitaires (A.F. laboratory), institutional grants from Institut Pasteur, INSERM, Université Paris Diderot and the Agence Nationale de la Recherche (“Myeloten”; R.G. group), the Institut National du Cancer (R.G. group) and Université Sorbonne Paris Cité (“Mucocell”; R.G. group).

Author information

Authors and Affiliations



F.V., A.F. and E.V. devised and supervised the study, designed the research, and wrote the manuscript, with the help of the other co-authors; V.B., B.V. and B.N. designed the research, performed experiments and analyzed the data; C. Pip., T.P., M.P., N.Y., F.T., J.B., J.H.W.D., A.R. and R.G. performed the experiments and analyzed the data; and M.E., N.M., N.Z., C.F., G. M., D.M., S.B., A.D., H.S. and C. Pic. provided key expertise, reagents or samples.

Corresponding authors

Correspondence to Alain Fischer or Eric Vivier.

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Competing interests

E.V. is the cofounder of and a shareholder in Innate Pharma.

Integrated supplementary information

Supplementary Figure 1 Correlation analysis of the number of circulating ILCs in healthy subjects.

A Spearman test was used to analyze correlations between ILC subset counts in both healthy adult (n = 30) and pediatric patients (n = 29). * P < 0.01 and ** P < 0.0001.

Supplementary Figure 2 Circulating ILCs in patients with RAG1 deficiency.

Flow cytometric analysis of ILC subsets in human peripheral blood as shown in Fig. 1. Data are from one experiment per indicated samples.

Supplementary Figure 3 Expression of CD5 on ILC1s.

The cell-surface expression of CD5 was assessed by flow cytometry on ILC1s from the patients indicated. The results are expressed as the percentages of CD5+ ILC1 within total peripheral blood ILC1 defined as in Fig. 1. Individual colors represent individual patients. * P < 0.02. NS, not significant (* P > 0.05).

Supplementary Figure 4 Absence of intestinal NKp46+ ILCs in HSCT-treated patients with SCID.

Staining with anti-NKp46 and anti-CD3 antibodies on a representative duodenum biopsy specimen from a HSCT-treated SCID patient. Frozen sections were stained with polyclonal anti-NKp46 serum (green), and anti-CD3 mAb (red). Nuclei were counterstained with DAPI (gray). The data shown are representative of at least two independent experiments on the same patient sample. Scale bar, 100 μM

Supplementary Figure 5 Absence of tissue-resident ILCs in aplastic patients with SCID.

CD3, NKp46 and CD3, CD11b, ICOS stainings of indicated representative specimen from two aplastic RAG1 SCID patients. Scale bar, 50 μM.

Supplementary Figure 6 Reconstitution of ILCs after engraftment of adult multipotent progenitors into Rag2−/−Il2rg−/− host mice.

Multipotent progenitors were sorted from C57BL/6/J adult bone marrow. Both multipotent progenitors (MPP) and lymphoid primed multipotent progenitors (LMPP) were identified in the LSK fraction of the bone marrow. (a) Control of sorting purity. Flow cytometry analysis of (b) lung and (c) and small intestine lamina propria and (d) liver after the reconstitution of irradiated (left panel) and non-irradiated (right panel) CD45.1+ Rag2−/−Il2rg−/− recipient mice. By using CD45.1 and CD45.2 congenic markers, donor-derived (CD45.2+) hematopoietic populations were separated from their recipient (CD45.1+) counterparts. (b) The expression of CD49a and CD49b was assessed on liver NKp46+NK1.1+ populations, to identify ILC1 and NK cells respectively. (c) ILC2 from the lung were identified as LinGata3+IL7Rα+ cells co-expressing ICOS and ST2. ILC1 and NK cells from the lungs were identified as NKp46+NK1.1+IL7Rα+ and NKp46+NK1.1+IL7Rα- respectively (d) CD3, CD19, Thy1, CD4, NKp46, NK1.1, CD49a, CD49b, KLRG1, RORγt, Gata3 and IL7Rα were assessed in the small intestine (SI) to identify NK, ILC1, ILC2 and ILC3 populations of the lamina propria. The data shown are representative of two experiments with three mice for each condition.

Supplementary Figure 7 Normal values of γδT cells and invariant NKT cells in HSCT-treated patients with SCID.

(a) Absolute numbers of γδT cells are indicated as cell numbers per microliter of peripheral blood in children and adult SCID patients (colored circles) or CDC patients (colored triangles).(b) iNKT cells were defined as Vα24+Vβ11+ T cells within the CD3+ gate. A representative staining corresponding to P9 is shown (left panel). The percentage of iNKT among CD3+ T cells has been determined for 5 patients (right panel). Dashed lines represent normal ranges of peripheral blood iNKT in healthy volunteers as previously described1. Individual colors represent individual patients, NS, not significant (* P > 0.05).

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Vély, F., Barlogis, V., Vallentin, B. et al. Evidence of innate lymphoid cell redundancy in humans. Nat Immunol 17, 1291–1299 (2016).

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