Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

THEMIS enhances TCR signaling and enables positive selection by selective inhibition of the phosphatase SHP-1

Nature Immunology volume 18, pages 433–441 (2017)Cite this article

Subjects

An Erratum to this article was published on 18 May 2017

This article has been updated

Abstract

THEMIS, a T cell–specific protein with high expression in CD4+CD8+ thymocytes, has a crucial role in positive selection and T cell development. THEMIS lacks defined catalytic domains but contains two tandem repeats of a distinctive module of unknown function (CABIT). Here we found that THEMIS directly regulated the catalytic activity of the tyrosine phosphatase SHP-1. This action was mediated by the CABIT modules, which bound to the phosphatase domain of SHP-1 and promoted or stabilized oxidation of SHP-1's catalytic cysteine residue, which inhibited the tyrosine-phosphatase activity of SHP-1. Deletion of SHP-1 alleviated the developmental block in Themis−/− thymocytes. Thus, THEMIS facilitates thymocyte positive selection by enhancing the T cell antigen receptor signaling response to low-affinity ligands.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: THEMIS binds directly to SHP-1.
Figure 2: THEMIS directly inhibits the tyrosine-phosphatase activity of SHP-1.
Figure 3: Inhibition of the PTP activity of SHP-1 restores the in vitro maturation of Themis−/− thymocytes.
Figure 4: Deletion of Ptpn6 alleviates the developmental block in Themis−/− thymocytes.
Figure 5: THEMIS promotes or stabilizes the oxidation of SHP-1.
Figure 6: The diminished tyrosine-phosphorylation of SHP-1 in Themis−/− thymocytes is caused by increased PTP activity of SHP-1.
Figure 7: Attenuated TCR signaling responses in Themis−/− thymocytes in the presence of ROS.

Similar content being viewed by others

Change history

  • 07 March 2017

    In the version of this article initially published online, in the second sentence of the first paragraph of the third subsection of Results ('Deletion of Ptpn6 restores T cell development in Themis–/– mice'), the TCR chain is identified incorrectly as 'CD3'; that phrase should read "...antibody to the TCR invariant chain CD3ε (anti-CD3ε)..." instead. In the legend to Figure 3, the P value (< 0.005) was incorrect; the correct value is P < 0.05. Also, in the final sentence of that legend, the directions '(left)' and '(right)' are incorrect; that should read "Data are representative of (top) or from (bottom) four experiments..." instead. In Figure 4a, the numbers along the horizontal axes are incorrectly vertical; they should be horizontal instead. In Figure 4b, the labels along the vertical axes of the second and fourth plots incorrectly include '(%)'; the correct label is 'CD8SP cells (×106)' only. In the third sentence of the first paragraph of the fifth subsection of Results ('p-SHP-1 does not correspond with PTP activity'), the word 'of' is missing; this should read "The lower abundance of p-SHP-1..." instead. In the legend to Figure 5c, the antibody is incorrectly set off in commas; that should read "...immunoprecipitated with anti-SHP-1 from..." instead. Finally, Figure 7e is too large and should be the same size as all other panels in that figure. The errors have been corrected in the print, PDF and HTML versions of this article.

References

  1. Koch, U. & Radtke, F. Mechanisms of T cell development and transformation. Annu. Rev. Cell Dev. Biol. 27, 539–562 (2011).

    Article  CAS  PubMed  Google Scholar 

  2. Aifantis, I., Mandal, M., Sawai, K., Ferrando, A. & Vilimas, T. Regulation of T-cell progenitor survival and cell-cycle entry by the pre-T-cell receptor. Immunol. Rev. 209, 159–169 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. Starr, T.K., Jameson, S.C. & Hogquist, K.A. Positive and negative selection of T cells. Annu. Rev. Immunol. 21, 139–176 (2003).

    Article  CAS  PubMed  Google Scholar 

  4. Hogquist, K.A. & Jameson, S.C. The self-obsession of T cells: how TCR signaling thresholds affect fate 'decisions' and effector function. Nat. Immunol. 15, 815–823 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Brownlie, R.J. & Zamoyska, R. T cell receptor signalling networks: branched, diversified and bounded. Nat. Rev. Immunol. 13, 257–269 (2013).

    Article  CAS  PubMed  Google Scholar 

  6. Pao, L.I., Badour, K., Siminovitch, K.A. & Neel, B.G. Nonreceptor protein-tyrosine phosphatases in immune cell signaling. Annu. Rev. Immunol. 25, 473–523 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Lesourne, R. et al. Themis, a T cell-specific protein important for late thymocyte development. Nat. Immunol. 10, 840–847 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Fu, G. et al. Themis controls thymocyte selection through regulation of T cell antigen receptor-mediated signaling. Nat. Immunol. 10, 848–856 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Johnson, A.L. et al. Themis is a member of a new metazoan gene family and is required for the completion of thymocyte positive selection. Nat. Immunol. 10, 831–839 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kakugawa, K. et al. A novel gene essential for the development of single positive thymocytes. Mol. Cell. Biol. 29, 5128–5135 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Patrick, M.S. et al. Gasp, a Grb2-associating protein, is critical for positive selection of thymocytes. Proc. Natl. Acad. Sci. USA 106, 16345–16350 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Paster, W. et al. GRB2-mediated recruitment of THEMIS to LAT is essential for thymocyte development. J. Immunol. 190, 3749–3756 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lesourne, R. et al. Interchangeability of Themis1 and Themis2 in thymocyte development reveals two related proteins with conserved molecular function. J. Immunol. 189, 1154–1161 (2012).

    Article  CAS  PubMed  Google Scholar 

  14. Zvezdova, E. et al. Themis1 enhances T cell receptor signaling during thymocyte development by promoting Vav1 activity and Grb2 stability. Sci. Signal. 9, ra51 (2016).

    Article  PubMed  CAS  Google Scholar 

  15. Paster, W. et al. A THEMIS:SHP1 complex promotes T-cell survival. EMBO J. 34, 393–409 (2015).

    Article  CAS  PubMed  Google Scholar 

  16. Fu, G. et al. Themis sets the signal threshold for positive and negative selection in T-cell development. Nature 504, 441–445 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gascoigne, N.R. & Acuto, O. THEMIS: a critical TCR signal regulator for ligand discrimination. Curr. Opin. Immunol. 33, 86–92 (2015).

    Article  CAS  PubMed  Google Scholar 

  18. Okada, T. et al. Differential function of Themis CABIT domains during T cell development. PLoS One 9, e89115 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Davey, G.M. et al. Preselection thymocytes are more sensitive to T cell receptor stimulation than mature T cells. J. Exp. Med. 188, 1867–1874 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zvezdova, E. et al. In vivo functional mapping of the conserved protein domains within murine Themis1. Immunol. Cell Biol. 92, 721–728 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Cibotti, R., Punt, J.A., Dash, K.S., Sharrow, S.O. & Singer, A. Surface molecules that drive T cell development in vitro in the absence of thymic epithelium and in the absence of lineage-specific signals. Immunity 6, 245–255 (1997).

    Article  CAS  PubMed  Google Scholar 

  22. Pathak, M.K. & Yi, T. Sodium stibogluconate is a potent inhibitor of protein tyrosine phosphatases and augments cytokine responses in hemopoietic cell lines. J. Immunol. 167, 3391–3397 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. Lee, P.P. et al. A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival. Immunity 15, 763–774 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Huyer, G. et al. Mechanism of inhibition of protein-tyrosine phosphatases by vanadate and pervanadate. J. Biol. Chem. 272, 843–851 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Karisch, R. & Neel, B.G. Methods to monitor classical protein-tyrosine phosphatase oxidation. FEBS J. 280, 459–475 (2013).

    Article  CAS  PubMed  Google Scholar 

  26. Michalek, R.D. et al. The requirement of reversible cysteine sulfenic acid formation for T cell activation and function. J. Immunol. 179, 6456–6467 (2007).

    Article  CAS  PubMed  Google Scholar 

  27. Singh, D.K. et al. The strength of receptor signaling is centrally controlled through a cooperative loop between Ca2+ and an oxidant signal. Cell 121, 281–293 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Capasso, M. et al. HVCN1 modulates BCR signal strength via regulation of BCR-dependent generation of reactive oxygen species. Nat. Immunol. 11, 265–272 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lorenz, U. SHP-1 and SHP-2 in T cells: two phosphatases functioning at many levels. Immunol. Rev. 228, 342–359 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Ozawa, T., Nakata, K., Mizuno, K. & Yakura, H. Negative autoregulation of Src homology region 2-domain-containing phosphatase-1 in rat basophilic leukemia-2H3 cells. Int. Immunol. 19, 1049–1061 (2007).

    Article  CAS  PubMed  Google Scholar 

  31. Devadas, S., Zaritskaya, L., Rhee, S.G., Oberley, L. & Williams, M.S. Discrete generation of superoxide and hydrogen peroxide by T cell receptor stimulation: selective regulation of mitogen-activated protein kinase activation and fas ligand expression. J. Exp. Med. 195, 59–70 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Los, M. et al. IL-2 gene expression and NF-κB activation through CD28 requires reactive oxygen production by 5-lipoxygenase. EMBO J. 14, 3731–3740 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Jackson, S.H., Devadas, S., Kwon, J., Pinto, L.A. & Williams, M.S. T cells express a phagocyte-type NADPH oxidase that is activated after T cell receptor stimulation. Nat. Immunol. 5, 818–827 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Pani, G., Colavitti, R., Borrello, S. & Galeotti, T. Endogenous oxygen radicals modulate protein tyrosine phosphorylation and JNK-1 activation in lectin-stimulated thymocytes. Biochem. J. 347, 173–181 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Plas, D.R. et al. Direct regulation of ZAP-70 by SHP-1 in T cell antigen receptor signaling. Science 272, 1173–1176 (1996).

    Article  CAS  PubMed  Google Scholar 

  36. Halliwell, B. Cell culture, oxidative stress, and antioxidants: avoiding pitfalls. Biomed. J. 37, 99–105 (2014).

    PubMed  Google Scholar 

  37. Stefanova, I. et al. TCR ligand discrimination is enforced by competing ERK positive and SHP-1 negative feedback pathways. Nat. Immunol. 4, 248–254 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Andersen, J.N. et al. Structural and evolutionary relationships among protein tyrosine phosphatase domains. Mol. Cell. Biol. 21, 7117–7136 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Tanner, J.J., Parsons, Z.D., Cummings, A.H., Zhou, H. & Gates, K.S. Redox regulation of protein tyrosine phosphatases: structural and chemical aspects. Antioxid. Redox Signal. 15, 77–97 (2011).

    Article  CAS  PubMed  Google Scholar 

  40. Pregel, M.J. & Storer, A.C. Active site titration of the tyrosine phosphatases SHP-1 and PTP1B using aromatic disulfides. Reaction with the essential cysteine residue in the active site. J. Biol. Chem. 272, 23552–23558 (1997).

    Article  CAS  PubMed  Google Scholar 

  41. Chen, C.Y., Willard, D. & Rudolph, J. Redox regulation of SH2-domain-containing protein tyrosine phosphatases by two backdoor cysteines. Biochemistry 48, 1399–1409 (2009).

    Article  CAS  PubMed  Google Scholar 

  42. Smith-Garvin, J.E., Koretzky, G.A. & Jordan, M.S. T cell activation. Annu. Rev. Immunol. 27, 591–619 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Bunda, S. et al. Inhibition of SHP2-mediated dephosphorylation of Ras suppresses oncogenesis. Nat. Commun. 6, 8859 (2015).

    Article  CAS  PubMed  Google Scholar 

  44. Fang, X. et al. Shp2 activates Fyn and Ras to regulate RBL-2H3 mast cell activation following FcepsilonRI aggregation. PLoS One 7, e40566 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Moon, E.Y., Han, Y.H., Lee, D.S., Han, Y.M. & Yu, D.Y. Reactive oxygen species induced by the deletion of peroxiredoxin II (PrxII) increases the number of thymocytes resulting in the enlargement of PrxII-null thymus. Eur. J. Immunol. 34, 2119–2128 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. Jin, R. et al. Trx1/TrxR1 system regulates post-selected DP thymocytes survival by modulating ASK1-JNK/p38 MAPK activities. Immunol. Cell Biol. 93, 744–752 (2015).

    Article  CAS  PubMed  Google Scholar 

  47. Simeoni, L. & Bogeski, I. Redox regulation of T-cell receptor signaling. Biol. Chem. 396, 555–568 (2015).

    Article  CAS  PubMed  Google Scholar 

  48. Pao, L.I. et al. B cell-specific deletion of protein-tyrosine phosphatase Shp1 promotes B-1a cell development and causes systemic autoimmunity. Immunity 27, 35–48 (2007).

    Article  CAS  PubMed  Google Scholar 

  49. Jang, I.K. et al. Grb2 functions at the top of the T-cell antigen receptor-induced tyrosine kinase cascade to control thymic selection. Proc. Natl. Acad. Sci. USA 107, 10620–10625 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank M. Muschen (University of California, San Francisco) for Ptpn6flox/flox mice; H. Gu (McGill University) for Grb2fl/fl mice; A. Ullrich (Max-Plank Institute, Germany) for Ptpn6 cDNA; L. Tautz (Sanford-Burnham Medical Research Institute) for Ptpn7 cDNA; J. Chernoff (Fox Chase Cancer Center) for plasmid encoding hemagglutinin-tagged PTPN1; and A. Bhandoola, R. Bosselut, R. Cornall, K. Pfeifer and A. Singer for critical review of the manuscript. Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (1ZIAHD001803 to P.E.L.) and by the Intramural Research Program of the National Library of Medicine (L.A.).

Author information

Authors and Affiliations

  1. Section on Hematopoiesis and Lymphocyte Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

    Seeyoung Choi, Claude Warzecha, Ekaterina Zvezdova, Jan Lee & Paul E Love

  2. Centre de Physiopathologie de Toulouse Purpan, Toulouse, France

    Jérémy Argenty & Renaud Lesourne

  3. Institut National de la Santé et de la Recherche Médicale, U1043, Centre National de la Recherche Scientifique, U5282, and Université de Toulouse, Université Paul Sabatier, Toulouse, France

    Jérémy Argenty & Renaud Lesourne

  4. National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USA

    L Aravind

Authors
  1. Seeyoung Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Claude Warzecha
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ekaterina Zvezdova
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jan Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jérémy Argenty
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Renaud Lesourne
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. L Aravind
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Paul E Love
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.C., C.W., E.Z., J.L. and J.A. performed the experiments; S.C., R.L. and P.E.L. were responsible for the concept and experimental design; L.A. performed proteomics, protein modeling and evolutionary analysis for the CABIT module and CABIT proteins; and P.E.L. wrote the manuscript.

Corresponding author

Correspondence to Paul E Love.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 THEMIS selectively binds to SHP-1 and SHP-2.

a, THEMIS binds to SHP-1 but not PTPN1 or PTPN7. HEK-293 cells were transfected with plasmids encoding Flag-tagged THEMIS plus plasmids encoding SHP-1 (left), PTPN7 (middle) or PTPN1 (right). Cell lysates of transfected cells were analyzed directly by SDS-PAGE and immunoblotting (lower blots) or incubated with anti-Flag and immunoprecipitated proteins were subjected to SDS-PAGE then immunoblotted with the indicated antibodies (upper blots). One representative of two experiments. b, THEMIS binds to SHP-2. HEK-293 cells were transfected with plasmids encoding GST or GST-THEMIS. Lower blot is endogenous SHP-2. Upper blots show GST or GST-THEMIS pull downs blotted with anti-SHP-2 or anti-GST. One representative of two experiments. c,d,THEMIS CABIT modules bind to the SHP-1 PTP domain. Purified His-tagged CABIT-1 (THEMIS-1-260) or CABIT-2 (THEMIS-260-493) and GST-ΔSH2-SHP-1 proteins were incubated in GST binding buffer then incubated with glutathione beads. Bound proteins were subjected to SDS-PAGE and then blotted with anti-His. e, THEMIS-C-A binds SHP-1. CABIT-1 and CABIT-2 core domain cysteine residues were mutated to alanine (C-A). Plasmids encoding THEMIS, THEMIS-C-A and SHP-1 were transfected into HEK-293 cells in the combinations indicated. Flag (THEMIS) immunoprecipitated proteins (upper blot) or cell lysates (lower blot) were blotted for SHP-1. One representative of two experiments.

Supplementary Figure 2 Deletion of Ptpn6 ‘rescues’ T cell development in Themis-/- mice.

a, Flow cytometry analysis of thymocytes (left) or splenocytes (right) from mice of the indicated genotype. Thymus: two parameter plots show CD4 versus CD8 staining of total thymocytes or gated TCRhi thymocytes. Spleen: two parameter plots show CD4 versus CD8 staining of total spleen cells or CD62L versus CD44 staining of gated CD4 SP cells. Percentage of cells in the indicated quadrants are shown. b, Expression of THEMIS and SHP-1 in total thymocytes from the experiment shown. c, CD4 SP and CD8 SP T cell counts (x106) from thymus and spleen of the indicated mice (see a). Data shown are representative of 3 independent experiments. Error bars are SD, t-test 2-tailed, equal variance. *P<.05, **P<.01, ***P<.005. n.s., not significant (P >.05).

Supplementary Figure 3 THEMIS promotes or stabilizes active-site oxidation of SHP-1.

a, SHP-1 oxidation by pervanadate (PV) in vitro. Repeat of experiment shown in Fig. 5a. b, SHP-1 oxidation by PV in transfected HEK293 cells. Repeat of experiment shown in Fig. 5b. c, SHP-1 is rapidly oxidized in thymocytes lysed in buffer lacking PTP inhibitors. Lanes 1-3, thymocytes from the indicated mice were lysed on ice in degassed oxidation lysis buffer containing IAP-Bio to immediately label reduced PTP active site cysteines. Lanes 4-6, thymocytes were lysed on ice for 20 min in lysis buffer without PTP inhibitors then IAP-Bio was added. All lysates were incubated for 1 hr with anti-SHP-1 and immunoprecipitated proteins were analyzed by immunoblotting with Streptavidin (SA)-HRP to detect biotinylated protein. d, PTP activity of SHP-1 immunoprecipitated from thymocyte cell lysates. Cells were lysed in degassed PTP lysis buffer without PTP inhibitors for 20 min on ice, anti-SHP-1 was added and lysates were rotated for 1 h at 4°C. Immunoprecipitated SHP-1 was assayed for PTP activity as described in methods. e, SHP-1 oxidation in vivo. Repeat of experiment shown in Fig. 5d.

Supplementary Figure 4 Themis−/− signaling defects are revealed in the presence of ROS.

a, TCR stimulation does not induce ROS production in thymocytes. Freshly harvested thymocytes from B6 mice were unstimulated or stimulated for 5 min with anti-CD3+CD4, anti-CD3+CD28 or phorbol 12-myristate 13-acetate (PMA), lysed, and Reactive Oxygen Species (ROS) were measured by chemiluminescence assay. Results are from three experiments. b, Reduced induction of p-ZAP-70 in peptide stimulated Themis−/− thymocytes. Purified CD4+CD8+ thymocytes from MHCII (I-A)−/− mice expressing the OTII-TCR were rested for three hours at 5x106 cells/ml in RPMI at 37°C prior stimulation. Purified splenic B cells were pulsed for 2h at 37°C with 100ng/ml of OVA peptide (ISQAVHAAHAEINEAGR) or no peptide (NP) in RPMI supplemented with 5% FBS and 10mM HEPES. For stimulation, pulsed B cells and thymocytes were mixed at a ratio of 1/10 and spun at 5000 x g prior incubation at 37°C for the indicated time. Cells were lysed in Standard lysis buffer then subjected to SDS-PAGE and immunoblotted with the indicated antibodies. Data shown are representative of 2 independent experiments.

Supplementary Figure 5 Inhibition of SHP-1 by THEMIS is attenuated by the ROS scavenger N-acetyl-l-cysteine (NAC).

a, THEMIS-mediated inhibition of SHP-1 is attenuated by NAC in transfected HEK-293 cells. HEK-293 cells were transfected with plasmid encoding the protein tyrosine kinase SYK, a target of SHP-1, plus or minus plasmids encoding SHP-1 and THEMIS. Transfected cells were treated or not overnight with N-acetyl-cysteine (NAC) before lysis, SDS-PAGE and western blotting with the indicated antibodies. One representative of 2 experiments. b, THEMIS-mediated inhibition of SHP-1 in vitro is partially attenuated in the presence of NAC. SHP-1 was assayed for PTP activity in the presence or absence of THEMIS and NAC as indicated. PTP assay was performed as is described in Methods. Bar graphs show means +/- SD, t-test, two-tailed, equal variance. n=3 each. ***P<.005, ****P<.001.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5 (PDF 849 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Choi, S., Warzecha, C., Zvezdova, E. et al. THEMIS enhances TCR signaling and enables positive selection by selective inhibition of the phosphatase SHP-1. Nat Immunol 18, 433–441 (2017). https://doi.org/10.1038/ni.3692

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.3692

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing