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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BMC Pulmonary Medicine Open Access 12 October 2021
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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).
E.V. is the cofounder of and a shareholder in Innate Pharma.
Integrated supplementary information
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.
Flow cytometric analysis of ILC subsets in human peripheral blood as shown in Fig. 1. Data are from one experiment per indicated samples.
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).
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
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 Lin−Gata3+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). https://doi.org/10.1038/ni.3553
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