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Protein abundance of the cytokine receptor γc controls the thymic generation of innate-like T cells

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Abstract

Innate-like T (iT) cells comprise a population of immunoregulatory T cells whose effector function is imposed during their development in the thymus to provide protective immunity prior to antigen encounter. The molecular mechanism that drives the generation of iT cells remains unclear. Here, we report that the cytokine receptor γc plays a previously unappreciated role for thymic iT cells by controlling their cellular abundance, lineage commitment, and subset differentiation. As such, γc overexpression on thymocytes dramatically altered iT cell generation in the thymus, as it skewed the subset composition of invariant NKT (iNKT) cells and promoted the generation of IFNγ-producing innate CD8 T cells. Mechanistically, we found that the γc-STAT6 axis drives the differentiation of IL-4-producing iNKT cells, which in turn induced the generation of innate CD8 T cells. Collectively, these results reveal a cytokine-driven circuity of thymic iT cell differentiation that is controlled by the abundance of γc proteins.

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References

  1. Fink PJ, Hendricks DW (2011) Post-thymic maturation: young T cells assert their individuality. Nat Rev Immunol 11(8):544–549. https://doi.org/10.1038/nri3028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Seddon B, Yates AJ (2018) The natural history of naive T cells from birth to maturity. Immunol Rev 285(1):218–232. https://doi.org/10.1111/imr.12694

    Article  CAS  PubMed  Google Scholar 

  3. Alonzo ES, Sant’Angelo DB (2011) Development of PLZF-expressing innate T cells. Curr Opin Immunol 23(2):220–227. https://doi.org/10.1016/j.coi.2010.12.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Jameson SC, Lee YJ, Hogquist KA (2015) Innate memory T cells. Adv Immunol 126:173–213. https://doi.org/10.1016/bs.ai.2014.12.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Banach M, Robert J (2019) Evolutionary underpinnings of innate-like T cell interactions with cancer. Immunol Invest 48(7):737–758. https://doi.org/10.1080/08820139.2019.1631341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Vermijlen D, Prinz I (2014) Ontogeny of Innate T Lymphocytes - Some Innate Lymphocytes are More Innate than Others. Front Immunol 5:486. https://doi.org/10.3389/fimmu.2014.00486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Salou M, Legoux F, Lantz O (2021) MAIT cell development in mice and humans. Mol Immunol 130:31–36. https://doi.org/10.1016/j.molimm.2020.12.003

    Article  CAS  PubMed  Google Scholar 

  8. Weinreich MA, Odumade OA, Jameson SC, Hogquist KA (2010) T cells expressing the transcription factor PLZF regulate the development of memory-like CD8+ T cells. Nat Immunol 11(8):709–716. https://doi.org/10.1038/ni.1898

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Gascoigne NR, Rybakin V, Acuto O, Brzostek J (2016) TCR Signal Strength and T Cell Development. Annu Rev Cell Dev Biol 32:327–348. https://doi.org/10.1146/annurev-cellbio-111315-125324

    Article  CAS  PubMed  Google Scholar 

  10. Singer A, Adoro S, Park JH (2008) Lineage fate and intense debate: myths, models and mechanisms of CD4- versus CD8-lineage choice. Nat Rev Immunol 8(10):788–801. https://doi.org/10.1038/nri2416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zlotnik A, Moore TA (1995) Cytokine production and requirements during T-cell development. Curr Opin Immunol 7(2):206–213. https://doi.org/10.1016/0952-7915(95)80005-0

    Article  CAS  PubMed  Google Scholar 

  12. Waickman AT, Park JY, Park JH (2016) The common gamma-chain cytokine receptor: tricks-and-treats for T cells. Cell Mol Life Sci 73(2):253–269. https://doi.org/10.1007/s00018-015-2062-4

    Article  CAS  PubMed  Google Scholar 

  13. DiSanto JP, Muller W, Guy-Grand D, Fischer A, Rajewsky K (1995) Lymphoid development in mice with a targeted deletion of the interleukin 2 receptor gamma chain. Proc Natl Acad Sci USA 92(2):377–381. https://doi.org/10.1073/pnas.92.2.377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Park JY, Jo Y, Ko E, Luckey MA, Park YK, Park SH et al (2016) Soluble gammac cytokine receptor suppresses IL-15 signaling and impairs iNKT cell development in the thymus. Sci Rep 6:36962. https://doi.org/10.1038/srep36962

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. McCaughtry TM, Etzensperger R, Alag A, Tai X, Kurtulus S, Park JH et al (2012) Conditional deletion of cytokine receptor chains reveals that IL-7 and IL-15 specify CD8 cytotoxic lineage fate in the thymus. J Exp Med 209(12):2263–2276. https://doi.org/10.1084/jem.20121505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ligons DL, Hwang S, Waickman AT, Park JY, Luckey MA, Park JH (2018) RORgammat limits the amount of the cytokine receptor gammac through the prosurvival factor Bcl-xL in developing thymocytes. Sci Signal. https://doi.org/10.1126/scisignal.aam8939

    Article  PubMed  PubMed Central  Google Scholar 

  17. Sun Z, Unutmaz D, Zou YR, Sunshine MJ, Pierani A, Brenner-Morton S et al (2000) Requirement for RORgamma in thymocyte survival and lymphoid organ development. Science 288(5475):2369–2373. https://doi.org/10.1126/science.288.5475.2369

    Article  CAS  PubMed  Google Scholar 

  18. Kurebayashi S, Ueda E, Sakaue M, Patel DD, Medvedev A, Zhang F et al (2000) Retinoid-related orphan receptor gamma (RORgamma) is essential for lymphoid organogenesis and controls apoptosis during thymopoiesis. Proc Natl Acad Sci USA 97(18):10132–10137. https://doi.org/10.1073/pnas.97.18.10132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Crispe IN, Bevan MJ (1987) Expression and functional significance of the J11d marker on mouse thymocytes. J Immunol 138(7):2013–2018

    CAS  PubMed  Google Scholar 

  20. Starr TK, Jameson SC, Hogquist KA (2003) Positive and negative selection of T cells. Annu Rev Immunol 21:139–176. https://doi.org/10.1146/annurev.immunol.21.120601.141107

    Article  CAS  PubMed  Google Scholar 

  21. Yu Q, Park JH, Doan LL, Erman B, Feigenbaum L, Singer A (2006) Cytokine signal transduction is suppressed in preselection double-positive thymocytes and restored by positive selection. J Exp Med 203(1):165–175. https://doi.org/10.1084/jem.20051836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hong C, Luckey MA, Ligons DL, Waickman AT, Park JY, Kim GY et al (2014) Activated T cells secrete an alternatively spliced form of common gamma-chain that inhibits cytokine signaling and exacerbates inflammation. Immunity 40(6):910–923. https://doi.org/10.1016/j.immuni.2014.04.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Park JH, Adoro S, Guinter T, Erman B, Alag AS, Catalfamo M et al (2010) Signaling by intrathymic cytokines, not T cell antigen receptors, specifies CD8 lineage choice and promotes the differentiation of cytotoxic-lineage T cells. Nat Immunol 11(3):257–264. https://doi.org/10.1038/ni.1840

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lee YJ, Holzapfel KL, Zhu J, Jameson SC, Hogquist KA (2013) Steady-state production of IL-4 modulates immunity in mouse strains and is determined by lineage diversity of iNKT cells. Nat Immunol 14(11):1146–1154. https://doi.org/10.1038/ni.2731

    Article  CAS  PubMed  Google Scholar 

  25. Gordon SM, Carty SA, Kim JS, Zou T, Smith-Garvin J, Alonzo ES et al (2011) Requirements for eomesodermin and promyelocytic leukemia zinc finger in the development of innate-like CD8+ T cells. J Immunol 186(8):4573–4578. https://doi.org/10.4049/jimmunol.1100037

    Article  CAS  PubMed  Google Scholar 

  26. Weinreich MA, Takada K, Skon C, Reiner SL, Jameson SC, Hogquist KA (2009) KLF2 transcription-factor deficiency in T cells results in unrestrained cytokine production and upregulation of bystander chemokine receptors. Immunity 31(1):122–130. https://doi.org/10.1016/j.immuni.2009.05.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Huang W, August A (2015) The signaling symphony: T cell receptor tunes cytokine-mediated T cell differentiation. J Leukoc Biol 97(3):477–485. https://doi.org/10.1189/jlb.1RI0614-293R

    Article  CAS  PubMed  Google Scholar 

  28. Park JY, DiPalma DT, Kwon J, Fink J, Park JH (2019) Quantitative difference in PLZF protein expression determines iNKT lineage fate and controls innate CD8 T cell generation. Cell Rep 27(9):2548–2574. https://doi.org/10.1016/j.celrep.2019.05.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kovalovsky D, Uche OU, Eladad S, Hobbs RM, Yi W, Alonzo E et al (2008) The BTB-zinc finger transcriptional regulator PLZF controls the development of invariant natural killer T cell effector functions. Nat Immunol 9(9):1055–1064. https://doi.org/10.1038/ni.1641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Savage AK, Constantinides MG, Han J, Picard D, Martin E, Li B et al (2008) The transcription factor PLZF directs the effector program of the NKT cell lineage. Immunity 29(3):391–403. https://doi.org/10.1016/j.immuni.2008.07.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wei DG, Lee H, Park SH, Beaudoin L, Teyton L, Lehuen A et al (2005) Expansion and long-range differentiation of the NKT cell lineage in mice expressing CD1d exclusively on cortical thymocytes. J Exp Med 202(2):239–248. https://doi.org/10.1084/jem.20050413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. McNab FW, Berzins SP, Pellicci DG, Kyparissoudis K, Field K, Smyth MJ et al (2005) The influence of CD1d in postselection NKT cell maturation and homeostasis. J Immunol 175(6):3762–3768. https://doi.org/10.4049/jimmunol.175.6.3762

    Article  CAS  PubMed  Google Scholar 

  33. Benlagha K, Wei DG, Veiga J, Teyton L, Bendelac A (2005) Characterization of the early stages of thymic NKT cell development. J Exp Med 202(4):485–492. https://doi.org/10.1084/jem.20050456

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Pellicci DG, Hammond KJ, Uldrich AP, Baxter AG, Smyth MJ, Godfrey DI (2002) A natural killer T (NKT) cell developmental pathway iInvolving a thymus-dependent NK1.1(-)CD4(+) CD1d-dependent precursor stage. J Exp Med 195(7):835–844. https://doi.org/10.1084/jem.20011544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Townsend MJ, Weinmann AS, Matsuda JL, Salomon R, Farnham PJ, Biron CA et al (2004) T-bet regulates the terminal maturation and homeostasis of NK and Valpha14i NKT cells. Immunity 20(4):477–494. https://doi.org/10.1016/s1074-7613(04)00076-7

    Article  CAS  PubMed  Google Scholar 

  36. Gordy LE, Bezbradica JS, Flyak AI, Spencer CT, Dunkle A, Sun J et al (2011) IL-15 regulates homeostasis and terminal maturation of NKT cells. J Immunol 187(12):6335–6345. https://doi.org/10.4049/jimmunol.1003965

    Article  CAS  PubMed  Google Scholar 

  37. Crosby CM, Kronenberg M (2018) Tissue-specific functions of invariant natural killer T cells. Nat Rev Immunol 18(9):559–574. https://doi.org/10.1038/s41577-018-0034-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lai D, Zhu J, Wang T, Hu-Li J, Terabe M, Berzofsky JA et al (2011) KLF13 sustains thymic memory-like CD8(+) T cells in BALB/c mice by regulating IL-4-generating invariant natural killer T cells. J Exp Med 208(5):1093–1103. https://doi.org/10.1084/jem.20101527

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Tuttle KD, Krovi SH, Zhang J, Bedel R, Harmacek L, Peterson LK et al (2018) TCR signal strength controls thymic differentiation of iNKT cell subsets. Nat Commun 9(1):2650. https://doi.org/10.1038/s41467-018-05026-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Dashtsoodol N, Bortoluzzi S, Schmidt-Supprian M (2019) T Cell Receptor expression timing and signal strength in the functional differentiation of invariant natural killer T cells. Front Immunol 10:841. https://doi.org/10.3389/fimmu.2019.00841

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zhao M, Svensson MND, Venken K, Chawla A, Liang S, Engel I et al (2018) Altered thymic differentiation and modulation of arthritis by invariant NKT cells expressing mutant ZAP70. Nat Commun 9(1):2627. https://doi.org/10.1038/s41467-018-05095-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Azzam HS, Grinberg A, Lui K, Shen H, Shores EW, Love PE (1998) CD5 expression is developmentally regulated by T cell receptor (TCR) signals and TCR avidity. J Exp Med 188(12):2301–2311. https://doi.org/10.1084/jem.188.12.2301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Pitcher LA, Young JA, Mathis MA, Wrage PC, Bartok B, van Oers NS (2003) The formation and functions of the 21- and 23-kDa tyrosine-phosphorylated TCR zeta subunits. Immunol Rev 191:47–61. https://doi.org/10.1034/j.1600-065x.2003.00003.x

    Article  CAS  PubMed  Google Scholar 

  44. Lin JX, Leonard WJ (2018) The common cytokine receptor gamma Chain Family of Cytokines. Cold Spring Harb Perspect Biol. https://doi.org/10.1101/cshperspect.a028449

    Article  PubMed  PubMed Central  Google Scholar 

  45. Hou J, Schindler U, Henzel WJ, Ho TC, Brasseur M, McKnight SL (1994) An interleukin-4-induced transcription factor: IL-4 Stat. Science 265(5179):1701–1706. https://doi.org/10.1126/science.8085155

    Article  CAS  PubMed  Google Scholar 

  46. Rochman Y, Spolski R, Leonard WJ (2009) New insights into the regulation of T cells by gamma(c) family cytokines. Nat Rev Immunol 9(7):480–490. https://doi.org/10.1038/nri2580

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Hogquist K, Georgiev H (2020) Recent advances in iNKT cell development. F1000Res. https://doi.org/10.12688/f1000research.21378.1

    Article  PubMed  PubMed Central  Google Scholar 

  48. Kwon DI, Lee YJ (2017) Lineage differentiation program of invariant natural killer T Cells. Immune Netw 17(6):365–377. https://doi.org/10.4110/in.2017.17.6.365

    Article  PubMed  PubMed Central  Google Scholar 

  49. Joseph C, Klibi J, Amable L, Comba L, Cascioferro A, Delord M et al (2019) TCR density in early iNKT cell precursors regulates agonist selection and subset differentiation in mice. Eur J Immunol 49(6):894–910. https://doi.org/10.1002/eji.201848010

    Article  CAS  PubMed  Google Scholar 

  50. Lazarevic V, Zullo AJ, Schweitzer MN, Staton TL, Gallo EM, Crabtree GR et al (2009) The gene encoding early growth response 2, a target of the transcription factor NFAT, is required for the development and maturation of natural killer T cells. Nat Immunol 10(3):306–313. https://doi.org/10.1038/ni.1696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Seiler MP, Mathew R, Liszewski MK, Spooner CJ, Barr K, Meng F et al (2012) Elevated and sustained expression of the transcription factors Egr1 and Egr2 controls NKT lineage differentiation in response to TCR signaling. Nat Immunol 13(3):264–271. https://doi.org/10.1038/ni.2230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Leonard WJ, Lin JX, O’Shea JJ (2019) The gammac family of cytokines: basic biology to therapeutic ramifications. Immunity 50(4):832–850. https://doi.org/10.1016/j.immuni.2019.03.028

    Article  CAS  PubMed  Google Scholar 

  53. Buechel HM, Stradner MH, D’Cruz LM (2015) Stages versus subsets: invariant natural killer T cell lineage differentiation. Cytokine 72(2):204–209. https://doi.org/10.1016/j.cyto.2014.12.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Havenar-Daughton C, Li SM, Benlagha K, Marie JC (2012) Development and function of murine ROR gamma t(+) iNKT cells are under TGF-beta signaling control. Blood 119(15):3486–3494. https://doi.org/10.1182/blood-2012-01-401604

    Article  CAS  PubMed  Google Scholar 

  55. Lee JY, Hamilton SE, Akue AD, Hogquist KA, Jameson SC (2013) Virtual memory CD8 T cells display unique functional properties. Proc Natl Acad Sci USA 110(33):13498–13503. https://doi.org/10.1073/pnas.1307572110

    Article  PubMed  PubMed Central  Google Scholar 

  56. White JT, Cross EW, Kedl RM (2017) Antigen-inexperienced memory CD8(+) T cells: where they come from and why we need them. Nat Rev Immunol 17(6):391–400. https://doi.org/10.1038/nri.2017.34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Costoya JA, Hobbs RM, Barna M, Cattoretti G, Manova K, Sukhwani M et al (2004) Essential role of Plzf in maintenance of spermatogonial stem cells. Nat Genet 36(6):653–659. https://doi.org/10.1038/ng1367

    Article  CAS  PubMed  Google Scholar 

  58. Park JY, Kwon J, Kim EY, Fink J, Kim HK, Park JH (2019) CD24(+) Cell depletion permits effective enrichment of thymic iNKT cells while preserving their subset composition. Immune Netw 19(2):e14. https://doi.org/10.4110/in.2019.19.e14

    Article  PubMed  PubMed Central  Google Scholar 

  59. Waickman AT, Ligons DL, Hwang S, Park JY, Lazarevic V, Sato N et al (2017) CD4 effector T cell differentiation is controlled by IL-15 that is expressed and presented in trans. Cytokine 99:266–274. https://doi.org/10.1016/j.cyto.2017.08.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Dr. Damian Kovalovsky (NCI) for ciritical comments on this manuscript. We also thank the EIB flow cytometry core for their expertise and help with FACS data acquisition and analysis.

Funding

This study was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH, and by a National Research Foundation of Korea grant (NRF-2018R1A5A2024418) funded by the Korean government MSIT (Ministry of Science and ICT).

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  1. Joo-Young Park and Hee Yeun Won have contributed equally to this work.

Authors and Affiliations

  1. Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, NIH, Building 10, Room 5B17, 10 Center Dr, Bethesda, MD, 20892, USA

    Joo-Young Park, Hee Yeun Won, Devon T. DiPalma & Jung-Hyun Park

  2. Department of Oral and Maxillofacial Surgery, Seoul National University Dental Hospital, Seoul National University School of Dentistry, Daehakno 101, Jongno-gu, Seoul, 03080, South Korea

    Joo-Young Park

  3. Department of Anatomy, Pusan National University School of Medicine, Yangsan, 626-870, South Korea

    Changwan Hong

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JYP and HW designed and performed the experiments, analyzed the data, and contributed to the writing of the manuscript. DTD and CH performed experiments and analyzed the data. JHP conceived the project, supervised the study, and wrote the manuscript.

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Correspondence to Jung-Hyun Park.

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Approval of animal experiments was granted by the NCI Animal Care and Use Committee under the animal protocol number EIB-076 and ASP-421. All mice were cared for in accordance with the Public Health Service policy on human care and use of laboratory animals and NIH guidelines.

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Park, JY., Won, H.Y., DiPalma, D.T. et al. Protein abundance of the cytokine receptor γc controls the thymic generation of innate-like T cells. Cell. Mol. Life Sci. 79, 17 (2022). https://doi.org/10.1007/s00018-021-04067-3

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