A tissue checkpoint regulates type 2 immunity

Abstract

Group 2 innate lymphoid cells (ILC2s) and CD4+ type 2 helper T cells (TH2 cells) are defined by their similar effector cytokines, which together mediate the features of allergic immunity. We found that tissue ILC2s and TH2 cells differentiated independently but shared overlapping effector function programs that were mediated by exposure to the tissue-derived cytokines interleukin 25 (IL-25), IL-33 and thymic stromal lymphopoietin (TSLP). Loss of these three tissue signals did not affect lymph node priming, but abrogated the terminal differentiation of effector TH2 cells and adaptive lung inflammation in a T cell–intrinsic manner. Our findings suggest a mechanism by which diverse perturbations can activate type 2 immunity and reveal a shared local-tissue-elicited checkpoint that can be exploited to control both innate and adaptive allergic inflammation.

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Figure 1: Cytokine reporters mark innate and adaptive tissue effectors.
Figure 2: IL-5-producing cells drive type 2 immunity in the lungs but not in the draining lymph nodes.
Figure 3: Activation of adaptive type 2 immunity despite ILC2 deficiency.
Figure 4: Multiple epithelial cytokines are induced in tissues during type 2 immunity.
Figure 5: Tissue cytokines are not required for lymph node adaptive immunity.
Figure 6: Tissue-cytokine licensing of TH2 cells is cell intrinsic.
Figure 7: Cell-intrinsic epithelial cytokine signaling is sufficient for terminal differentiation of TH2 cells.

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References

  1. 1

    Spits, H. et al. Innate lymphoid cells–a proposal for uniform nomenclature. Nat. Rev. Immunol. 13, 145–149 (2013).

    CAS  Article  Google Scholar 

  2. 2

    Patel, N. et al. A2B adenosine receptor induces protective antihelminth type 2 immune responses. Cell Host Microbe 15, 339–350 (2014).

    Article  CAS  PubMed  Google Scholar 

  3. 3

    Doherty, T.A. et al. Lung type 2 innate lymphoid cells express cysteinyl leukotriene receptor 1, which regulates TH2 cytokine production. J. Allergy Clin. Immunol. 132, 205–213 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Halim, T.Y. et al. Group 2 innate lymphoid cells license dendritic cells to potentiate memory TH2 cell responses. Nat. Immunol. 17, 57–64 (2016).

    Article  CAS  PubMed  Google Scholar 

  5. 5

    Oliphant, C.J. et al. MHCII-mediated dialog between group 2 innate lymphoid cells and CD4+ T cells potentiates type 2 immunity and promotes parasitic helminth expulsion. Immunity 41, 283–295 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Pelly, V.S. et al. IL-4-producing ILC2s are required for the differentiation of TH2 cells following Heligmosomoides polygyrus infection. Mucosal Immunol. http://dx.doi.org/10.1038/mi.2016.4 (2016).

  7. 7

    Mirchandani, A.S. et al. Type 2 innate lymphoid cells drive CD4+ TH2 cell responses. J. Immunol. 192, 2442–2448 (2014).

    Article  CAS  PubMed  Google Scholar 

  8. 8

    Drake, L.Y., Iijima, K. & Kita, H. Group 2 innate lymphoid cells and CD4+ T cells cooperate to mediate type 2 immune response in mice. Allergy 69, 1300–1307 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Gold, M.J. et al. Group 2 innate lymphoid cells facilitate sensitization to local, but not systemic, TH2-inducing allergen exposures. J. Allergy Clin. Immunol. 133, 1142–1148 (2014).

    Article  CAS  Google Scholar 

  10. 10

    Liu, B., Lee, J.B., Chen, C.Y., Hershey, G.K. & Wang, Y.H. Collaborative interactions between type 2 innate lymphoid cells and antigen-specific CD4+ TH2 cells exacerbate murine allergic airway diseases with prominent eosinophilia. J. Immunol. 194, 3583–3593 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Liang, H.E. et al. Divergent expression patterns of IL-4 and IL-13 define unique functions in allergic immunity. Nat. Immunol. 13, 58–66 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Finkelman, F.D. et al. Interleukin-4- and interleukin-13-mediated host protection against intestinal nematode parasites. Immunol. Rev. 201, 139–155 (2004).

    Article  CAS  Google Scholar 

  13. 13

    Mohrs, M., Shinkai, K., Mohrs, K. & Locksley, R.M. Analysis of type 2 immunity in vivo with a bicistronic IL-4 reporter. Immunity 15, 303–311 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. 14

    Nussbaum, J.C. et al. Type 2 innate lymphoid cells control eosinophil homeostasis. Nature 502, 245–248 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Buenrostro, J.D., Giresi, P.G., Zaba, L.C., Chang, H.Y. & Greenleaf, W.J. Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. Nat. Methods 10, 1213–1218 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Bando, J.K., Liang, H.E. & Locksley, R.M. Identification and distribution of developing innate lymphoid cells in the fetal mouse intestine. Nat. Immunol. 16, 153–160 (2015).

    Article  CAS  PubMed  Google Scholar 

  17. 17

    Vahedi, G. et al. Super-enhancers delineate disease-associated regulatory nodes in T cells. Nature 520, 558–562 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Sonnenberg, G.F. & Artis, D. Innate lymphoid cells in the initiation, regulation and resolution of inflammation. Nat. Med. 21, 698–708 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Halim, T.Y. et al. Group 2 innate lymphoid cells are critical for the initiation of adaptive T helper 2 cell-mediated allergic lung inflammation. Immunity 40, 425–435 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Wong, S.H. et al. Transcription factor RORα is critical for nuocyte development. Nat. Immunol. 13, 229–236 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Mebius, R.E. Organogenesis of lymphoid tissues. Nat. Rev. Immunol. 3, 292–303 (2003).

    Article  CAS  Google Scholar 

  22. 22

    Voehringer, D., Liang, H.E. & Locksley, R.M. Homeostasis and effector function of lymphopenia-induced “memory-like” T cells in constitutively T cell-depleted mice. J. Immunol. 180, 4742–4753 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Van Dyken, S.J. et al. Chitin activates parallel immune modules that direct distinct inflammatory responses via innate lymphoid type 2 and γδ T cells. Immunity 40, 414–424 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Wang, Y.H. et al. IL-25 augments type 2 immune responses by enhancing the expansion and functions of TSLP-DC-activated TH2 memory cells. J. Exp. Med. 204, 1837–1847 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Wang, Q., Du, J., Zhu, J., Yang, X. & Zhou, B. Thymic stromal lymphopoietin signaling in CD4+ T cells is required for TH2 memory. J. Allergy Clin. Immunol. 135, 781–91 e3 (2015).

    Article  CAS  PubMed  Google Scholar 

  26. 26

    Endo, Y. et al. The interleukin-33-p38 kinase axis confers memory T helper 2 cell pathogenicity in the airway. Immunity 42, 294–308 (2015).

    Article  CAS  PubMed  Google Scholar 

  27. 27

    Hung, L.Y. et al. IL-33 drives biphasic IL-13 production for noncanonical type 2 immunity against hookworms. Proc. Natl. Acad. Sci. USA 110, 282–287 (2013).

    Article  PubMed  Google Scholar 

  28. 28

    Fallon, P.G. et al. Identification of an interleukin (IL)-25-dependent cell population that provides IL-4, IL-5 and IL-13 at the onset of helminth expulsion. J. Exp. Med. 203, 1105–1116 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Palm, N.W. et al. Bee venom phospholipase A2 induces a primary type 2 response that is dependent on the receptor ST2 and confers protective immunity. Immunity 39, 976–985 (2013).

    Article  CAS  PubMed  Google Scholar 

  30. 30

    Matloubian, M. et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427, 355–360 (2004).

    Article  CAS  Google Scholar 

  31. 31

    Gauvreau, G.M. et al. Effects of an anti-TSLP antibody on allergen-induced asthmatic responses. N. Engl. J. Med. 370, 2102–2110 (2014).

    Article  CAS  Google Scholar 

  32. 32

    Shih, H.Y. et al. Developmental acquisition of regulomes underlies innate lymphoid cell functionality. Cell 165, 1120–1133 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Koues, O.I. et al. Distinct gene regulatory pathways for human innate versus adaptive lymphoid cells. Cell 165, 1134–1146 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Robinette, M.L. et al. Transcriptional programs define molecular characteristics of innate lymphoid cell classes and subsets. Nat. Immunol. 16, 306–317 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Guo, L. et al. Innate immunological function of TH2 cells in vivo. Nat. Immunol. 16, 1051–1059 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Neill, D.R. et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464, 1367–1370 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Cortez, V.S. et al. Transforming growth factor-β signaling guides the differentiation of innate lymphoid cells in salivary glands. Immunity 44, 1127–1139 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Gasteiger, G., Fan, X., Dikiy, S., Lee, S.Y. & Rudensky, A.Y. Tissue residency of innate lymphoid cells in lymphoid and nonlymphoid organs. Science 350, 981–985 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Wakim, L.M., Woodward-Davis, A. & Bevan, M.J. Memory T cells persisting within the brain after local infection show functional adaptations to their tissue of residence. Proc. Natl. Acad. Sci. USA 107, 17872–17879 (2010).

    Article  Google Scholar 

  40. 40

    Thome, J.J. et al. Spatial map of human T cell compartmentalization and maintenance over decades of life. Cell 159, 814–828 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Steinert, E.M. et al. Quantifying memory CD8 T cells reveals regionalization of immunosurveillance. Cell 161, 737–749 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    von Moltke, J. & Locksley, R.M. I-L-C-2 it: type 2 immunity and group 2 innate lymphoid cells in homeostasis. Curr. Opin. Immunol. 31, 58–65 (2014).

    Article  CAS  PubMed  Google Scholar 

  43. 43

    Reese, T.A. et al. Chitin induces accumulation in tissue of innate immune cells associated with allergy. Nature 447, 92–96 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Van Dyken, S.J. et al. Fungal chitin from asthma-associated home environments induces eosinophilic lung infiltration. J. Immunol. 187, 2261–2267 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Quinlan, A.R. & Hall, I.M. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26, 841–842 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Picard Tools. http://broadinstitute.github.io/picard/ (2015).

  48. 48

    Zhang, Y. et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 9, R137 (2008).

    PubMed  PubMed Central  Google Scholar 

  49. 49

    Langmead, B. & Salzberg, S.L. Fast gapped-read alignment with Bowtie 2. Nat. Methods 9, 357–359 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Trapnell, C., Pachter, L. & Salzberg, S.L. TopHat: discovering splice junctions with RNA-Seq. Bioinformatics 25, 1105–1111 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Flicek, P. et al. Ensembl 2014. Nucleic Acids Res. 42, D749–D755 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Anders, S. & Huber, W. Differential expression analysis for sequence count data. Genome Biol. 11, R106 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank M. Ji, K. Davis, M. Consengco and Z. Wang for technical expertise, A. Barczak and R. Barbeau for assistance with RNA-Seq, A. McKenzie, S. Akira, S. Ziegler and the US National Institutes of Health Tetramer Core Facility for reagents, and A. Abbas and M. Ansel for comments on the manuscript. Supported by the US National Institutes of Health (AI026918, AI030663, HL107202, HL128903, K08AI113143 and DP5-OD12178), the Howard Hughes Medical Institute and the Sandler Asthma Basic Research Center at the University of California San Francisco.

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Authors

Contributions

J.C.N. and S.J.V.D. performed experiments, interpreted data and wrote the manuscript. J.L., A.B.M. and G.E.H. provided experimental assistance. H.-E.L. generated reporter mouse strains. J.L.P. analyzed the RNA-Seq data. R.E.G. analyzed the ATAC-Seq data. D.J.E., A.M., C.J.Y. and R.M.L. directed the studies, and R.M.L. wrote the paper with J.C.N. and S.J.V.D.

Corresponding author

Correspondence to Richard M Locksley.

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Competing interests

A.M. is a scientific advisor for and has licensed technology to Juno Therapeutics. The Marson laboratory has sponsored research collaborations with Epinomics and Juno Therapeutics.

Integrated supplementary information

Supplementary Figure 1 Gating strategy and kinetics of lung type 2 immune cells during helminth infection.

a, Gating strategy for isolating lung CD4+ T cells, eosinophils, and ILC2s from live singlets in R5 reporter mice, where numbers in the plot are cell frequency in the gate. b, Fluorescence in the tdTomato channel and R5+ cells as a percentage of total CD4+ and innate lymphocytes in the lungs after N. brasiliensis (Nb) infection, presented as mean ± SEM. Data are (a) representative of at least 3 mice from at least 3 independent experiments or (b) pooled from 2 independent experiments for at least 3 mice per time point, represented as mean ± SEM. MFI, mean fluorescence intensity.

Supplementary Figure 2 Transcriptional and epigenetic profile of tissue ILC2s and TH2 cells.

a, Correlation matrix of Pearson correlation coefficients of genome-wide ATAC-Seq reads obtained from mediastinal lymph node and lung 4get+ T cells and from lung ILC2s 14 days after Nb infection and b, representative tracks from pooled ATAC-Seq reads aligning to Cd4, Arg1, and Il4, shown with identical vertical scale. c, Correlation matrix of reads within T cell super-enhancer regions in cells collected as in (a). d, RNA-Seq data from lung LinIL-5+ ILC2s and CD4+IL-5+ cells 14 d.p.i. with Nb. Shown are all genes (gray), differentially expressed genes (black; false discovery rate q < 0.05), and genes of interest that were significantly enriched in ILC2s (blue) and Th2 cells (red). Data are (a-c) from biological replicates as indicated; or (d) collected from 2 independent infections for a total of 6 ILC2 and 5 Th2 cell biological replicates. Lin, lineage.

Supplementary Figure 3 R5 reporter expression and Cre-mediated deletion of ILC2s or MHC class II expression on ILC2s.

a, R5 fluorescence in the indicated cell populations in the lungs and spleens of wild type and R5/R5 mice 3 days and 7 days after Nb infection, representative of at least 3 mice per group from at least 3 independent experiments. b, Number of LinThy1+CD25+IL33R+ cells in lungs of naïve R5/R5 and R5/R5 Deleter mice, n = 3 each group, representative of at least 3 independent experiments. c, Staining and quantification of PD-1+CXCR5+CD4+ T cells from mediastinal lymph nodes of R5/R5 and R5/R5 Deleter mice 12 days after Nb infection, pooled from two independent experiments for at least 5 mice per group. d, In correspondence with Fig. 3a-c, Rag1-deficient mice (either R5/R5 or R5/R5 Deleter) received no cells or naïve R5/+ CD4+ T cells before Nb infection. e, Representative flow cytometry staining of I-A (MHCII protein) on LinThy1+KLRG1+ ILC2s in the lung 7 days after Nb infection in R5/+, R5/+ H2-AB1 flox, and wild type mice, representative of at least 3 mice per genotype. Data pooled from 2-3 independent experiments for a total of at least 3 mice per group, represented as mean ± SEM. NKT, Natural Killer T cells, **, p < 0.01.

Supplementary Figure 4 Multiple tissue cytokines are required for local type 2 inflammation.

a, Lung eosinophils and b, intestinal worm counts in C57BL/6 wild-type (WT; n = 5), Il25–/– (IL25 KO; n = 5), Crlf2–/– (TSLPR KO; n = 4), Il1rl1–/– (ST2 KO; n = 6), Crlf2–/–Il25–/– (TSLPR/IL25 DKO; n = 6), Il1rl1–/–Il25–/– (ST2/IL25 DKO; n = 4) and triple-deficient (TKO; n = 5) mice 10 days after Nb infection. c, Lung Arg1+ macrophages in C57BL/6 WT and TKO mice 10 days after Nb infection, d, Intestinal worm counts in BALB/c WT or Crlf2–/–Il25–/–Il1rl1–/– TKO mice after Nb infection. e, Numbers of CD4+ T cells and f, percentage of CD4+ T cells expressing the 4get (GFP) allele in mediastinal lymph nodes (mLN) of BALB/c WT or TKO mice on a 4get reporter background and g, serum IgE amounts before and after administration of intranasal Aspergillus niger (Asp) or house dust mite (HDM) extracts. h, Number of CD4+ T cells and i, percentage of lung CD4+ T cells expressing 4get, and numbers of j, eosinophils and k, ILC2s in the lungs before and after Asp or HDM challenge. l, Number of lung eosinophils, m, Arg1+ macrophages, and n, neutrophils in C57BL/6 WT (n = 4), IL25 KO (n = 4), ST2 KO (n = 3), TSLPR KO (n = 5), and TKO mice (n = 5) after intranasal HDM. Data pooled from 2-3 independent experiments for a total of at least 3 mice per group, presented as mean ± SEM, *, p < 0.01; **, p < 0.001; ***, p < 0.0001, as compared to WT, †, p < 0.001, ST2/IL25DKO as compared to TKO.

Supplementary Figure 5 Tissue cytokines are not required for lymph node priming of adaptive immunity.

a, Representative flow cytometry and quantification of indicated mediastinal lymph node CD4+ T cell populations 3 days after Nb infection. b, Representative flow cytometry and c, quantification of CD4+ T cell populations in mesenteric lymph node (mLN) and peritoneal exudate cells (PEC) from 4get mice on WT and TKO backgrounds after intraperitoneal bee venom phospholipase A2 (bvPLA2) administration. Numbers in (b) indicate percentage of CD4+ T cells positive for 4get allele (GFP). d, Serum IgE amounts and e, number of eosinophils among PEC isolated from C57BL/6 WT (n = 6), ST2 KO (n = 3) and TKO mice (n = 10) after intraperitoneal administration of bvPLA2. f, Percent CD4+ T cells among live cells in mediastinal lymph nodes (mLN), blood, and lung of R5/4get and S13/4get mice and g, representative flow cytometry of CD4+ T cells from lung and mLN of S13/4get mice 7 days after infection with Nb and treated with FTY720 or vehicle. Numbers indicate percentage of CD4+ T cells positive for 4get (GFP) and S13 (huCD4) reporter alleles. Data pooled from 2-3 independent experiments for a total of at least 3 mice per group, presented as mean ± SEM; in (e), *, p < 0.05 **, p < 0.01 for TKO vs. ST2 KO and TKO vs. WT, respectively, and in (f), ***, p < 0.001, for vehicle vs. FTY720 treatment.

Supplementary Figure 6 Type 2 effector cytokine production from TH2 cells and ILC2s is abrogated in the absence of tissue cytokines.

a, IL-5 and IL-13 in Ion/PMA culture supernatants of lung ILC2s or 4get+CD4+ T cells sorted from Nb-infected mice at the indicated time points. b and d, Representative flow cytometry of lung CD4+ T cells and LinArg1+CD25+Thy1.2+ ILC2s from R5/S13 dual reporter mice on C57BL/6 WT and TKO backgrounds, with non-R5/S13 WT gating control at far left, b, 10 days post Nb infection (d.p.i.) and d, after intranasal HDM administration; numbers in quadrants are percent positive of each population as indicated. c and e, Total CD4+ T cells, ILC2s, and respective numbers of R5+ and S13+ subsets in the lungs of C57BL/6 WT and TKO mice c, 10 d.p.i.with Nb and e, after intranasal HDM administration. Data presented as mean ± SEM and are (a) pooled from 2 independent experiments for at least 4 mice per group or (b - e) pooled from 2 independent experiments for at least 3 mice per group. *, p < 0.01, **, p < 0.001; ***, p < 0.0001.

Supplementary Figure 7 T cell production of type 2 effector cytokines requires cell-intrinsic sensing of tissue cytokines in vivo.

a, Representative flow cytometry of mesenteric lymph node (mesLN) and peritoneal exudate (PEC) CD4+ T cells, and quantification of R5+ and S13+ PEC CD4+ T cells, from R5/S13 dual reporter mice on WT and TKO backgrounds after intraperitoneal bvPLA2 administration. Numbers in quadrants represent percent positive of total CD4+ T cells. b, Supernatant IL-5 and IL-13 and c, percentage of cells expressing 4get allele in CD4+ cells cultured under Th2-polarizing cultures from WT, TSLPR-deficient or TKO mice. d, Representative flow cytometry of transferred BALB/c WT and TKO CD4+ T cells isolated from mediastinal lymph node (medLN) and lung after intranasal papain administration. Numbers indicate percentage of cells positive for 4get allele (GFP). e and f, Numbers of total donor-derived CD4+ T cells and percentage 4get+ recovered from the e, medLN and f, lungs of Rag1-deficient recipients. g, IL-5 and IL-13 in supernatants of IL-7 or Ion/PMA cultures of lung 4get+CD4+ T cells sorted from papain-treated mice. h, Intestinal worm counts 10 days after infection with Nb in BALB/c TKO mice, with and without adoptively transferred WT CD4+ T cells. Data presented as mean ± SEM and represent at least 4 mice per group, pooled from 2 independent experiments. *, p < 0.01, **, p < 0.001; ***, p < 0.0001.

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Van Dyken, S., Nussbaum, J., Lee, J. et al. A tissue checkpoint regulates type 2 immunity. Nat Immunol 17, 1381–1387 (2016). https://doi.org/10.1038/ni.3582

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