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. 2016 Nov;17(11):1291-1299.
doi: 10.1038/ni.3553. Epub 2016 Sep 12.

Evidence of innate lymphoid cell redundancy in humans

Frédéric Vély  1   2 , Vincent Barlogis  3   4 , Blandine Vallentin  3 , Bénédicte Neven  4   5   6   7 , Christelle Piperoglou  1   2 , Mikael Ebbo  1   8 , Thibaut Perchet  9   10 , Maxime Petit  9   10 , Nadia Yessaad  11 , Fabien Touzot  5   12 , Julie Bruneau  5   13 , Nizar Mahlaoui  4   5   6   7 , Nicolas Zucchini  14 , Catherine Farnarier  2 , Gérard Michel  3 , Despina Moshous  4   5   6   7 , Stéphane Blanche  4   5   6   7 , Arnaud Dujardin  15 , Hergen Spits  16 , Jörg H W Distler  17 , Andreas Ramming  17 , Capucine Picard  4   5   6   7   18 , Rachel Golub  9   10 , Alain Fischer  4   5   6   7   19 , Eric Vivier  1   2
Affiliations

Evidence of innate lymphoid cell redundancy in humans

Frédéric Vély et al. Nat Immunol. 2016 Nov.

Erratum in

  • Corrigendum: Evidence of innate lymphoid cell redundancy in humans.
    Vély F, Barlogis V, Vallentin B, Neven B, Piperoglou C, Perchet T, Petit M, Yessaad N, Touzot F, Bruneau J, Mahlaoui N, Zucchini N, Farnarier C, Michel G, Moshous D, Blanche S, Dujardin A, Spits H, Distler JH, Ramming A, Picard C, Golub R, Fischer A, Vivier E. Vély F, et al. Nat Immunol. 2016 Nov 16;17(12):1479. doi: 10.1038/ni1216-1479b. Nat Immunol. 2016. PMID: 27849206 No abstract available.

Abstract

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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Conflict of interest statement

E.V. is the cofounder of and a shareholder in Innate Pharma. The other authors have no conflicting financial interest to declare.

Figures

Figure 1
Figure 1. Normal ILC levels in the peripheral blood of healthy pediatric and adult controls
(a) Flow cytometric analysis of ILCs in healthy human peripheral blood (PB). ILCs are defined within the CD45+ lymphocyte gate as Lin−CD127+ cells, with a lineage cocktail containing antibodies directed against CD3, CD19, CD14, TCRαβ, TCRγδ, CD94, CD16, FcεRI, CD34, CD123, and CD303. (b) ILC1, ILC2 and ILC3 counts in healthy children (blue, n = 29) and adults (orange, n = 30). Absolute numbers are indicated in numbers of cells per milliliter of peripheral blood. (c) NK cell counts in healthy children (blue, n = 29) and adults (orange, n = 30). NK cells are defined as CD3−CD56+ within the CD45+ lymphocyte gate. Absolute numbers of cells per microliter of peripheral blood are indicated. Distribution of ILC1, ILC2 and ILC3 within lymphocytes (d) or helper-like ILCs (e), is shown for cord blood (black), healthy children (blue) and healthy adults (orange). The subset distribution within the lymphocyte gate is represented in percentages. Medians, 10th and 90th percentiles are shown in box-plots. Outliers are indicated as dots. Data are from one experiment representative of more than 60 independent experiments with similar results (a), 29 and 30 experiments (b,c,d) or 7 experiments (e). NS, not significant (P > 0.05). * P=0.01 by Mann-Whitney test.
Figure 2
Figure 2. Severe ILC lymphopenia in JAK3 SCID patients
ILCs are defined within the CD45+ lymphocyte gate as Lin−CD127+ cells. Comparative ILC staining is shown for (a) 3 representative JAK3 SCID patients (P19, P20, P21) and (b) 2 RAG1 SCID patients (C11, C12) before HSCT are shown as controls.
Figure 3
Figure 3. Long-term ILC lymphopenia in HSCT-treated SCID patients
Absolute numbers (cells/µl) are indicated for CD3+ T cells, CD19+ B cells and CD3−CD56+ NK cells in the peripheral blood. Absolute numbers (cells/ml) are indicated for ILC subsets in the peripheral blood. (a) Black circles correspond to 6- to 14 year-old healthy controls (HC, n = 12), individual colors represent individual patients and correspond to 6- to 14 year-old IL2RG or JAK3 SCID patients (n = 7) and colored triangles correspond to control patients with complete donor chimerism (CDC, n = 5). (b) Healthy adult controls (HC, n = 26), adult IL2RG or JAK3 SCID patients (n = 11) and control patients with complete donor chimerism (CDC, n = 3) are shown as black squares, colored squares and colored triangles, respectively. NS, not significant (P > 0.05). * P=0.05 by Mann-Whitney test.
Figure 4
Figure 4. Absence of intestinal and skin ILCs in HSCT-treated SCID patients
CD3−NKp46+ and CD3−CD11b−ICOS+ staining was used to identify tissue-resident NKp46+ ILCs and ILC2 respectively in indicated organs. (a) left, duodenum sample from P5 (IL2RG) 10 years post non-myeloablative HSCT; middle, skin sample from P11 (JAK3) 18 years post non-myeloablative HSCT; right, colon from P16 (IL2RG) 5.5 years post non-myeloablative HSCT. (b) left, duodenum sample from C9 (RAG1) 15 months post-myeloablative HSCT; middle, skin sample from C10 (RAG2), 4 months post-myeloablative HSCT; right, colon sample from C9. (c) duodenum sample from P15 (IL2RG) 15 months post-myeloablative HSCT. (d) colon sample from P5, skin sample from P11, colon sample from C9 and skin sample from C10. Scale bar, 50 μm.
Figure 5
Figure 5. Reconstitution of ILCs after engraftment of adult multipotent progenitors into Rag2−/−Il2rg−/− deficient mice
Indicated ILC subsets from the lungs, liver and small intestine (SI) were analyzed by flow cytometry after the reconstitution of irradiated and non-irradiated CD45.1+ Rag2−/−Il2rg−/− recipient mice with multipotent progenitors sorted from CD45.2+ C57BL/6/J adult bone marrow. By using CD45.1 and CD45.2 congenic markers, donor-derived (CD45.2+) hematopoietic populations were separated from their recipient (CD45.1+) counterparts. ILC1 and NK cells from the lungs were identified as NKp46+NK1.1+IL7Rα+ and NKp46+NK1.1+IL7Rα− respectively. ILC2 from the lungs were identified as Lin−Gata3+IL7Rα+ cells co-expressing ICOS and ST2. The expression of CD49a and CD49b was assessed on liver NKp46+NK1.1+ populations, to identify ILC1 and NK cells respectively. CD3, CD19, Thy1, CD4, NKp46, NK1.1, CD49a, CD49b, KLRG1, RORγt, Gata3 and IL7Rα were assessed in SI to identify NK, ILC1, ILC2 and ILC3 populations of the lamina propria. Absolute numbers of indicated ILC populations in indicated organs; each symbol represents an individual mouse. The data shown are representative of two experiments with three mice for each condition. N.D.: None-detected. * P=0.02 by Mann-Whitney test.
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