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Nature communications
04 16, 2021;12 (1): 2308.

Classical MHC expression by DP thymocytes impairs the selection of non-classical MHC restricted innate-like T cells.

Hristo Georgiev, Changwei Peng, Matthew A Huggins, Stephen C Jameson, Kristin A Hogquist
Author Information
  1. Hristo Georgiev: Center for Immunology and Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, 55455, USA. ORCID
  2. Changwei Peng: Center for Immunology and Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, 55455, USA.
  3. Matthew A Huggins: Center for Immunology and Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, 55455, USA.
  4. Stephen C Jameson: Center for Immunology and Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, 55455, USA. ORCID
  5. Kristin A Hogquist: Center for Immunology and Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, 55455, USA. hogqu001@umn.edu. ORCID
PMID: 33863906 DOI: 10.1038/s41467-021-22589-z

Abstract

Conventional T cells are selected by peptide-MHC expressed by cortical epithelial cells in the thymus, and not by cortical thymocytes themselves that do not express MHC I or MHC II. Instead, cortical thymocytes express non-peptide presenting MHC molecules like CD1d and MR1, and promote the selection of PLZF iNKT and MAIT cells, respectively. Here, we report an inducible class-I transactivator mouse that enables the expression of peptide presenting MHC I molecules in different cell types. We show that MHC I expression in DP thymocytes leads to expansion of peptide specific PLZF innate-like (PIL) T cells. Akin to iNKT cells, PIL T cells differentiate into three functional effector subsets in the thymus, and are dependent on SAP signaling. We demonstrate that PIL and NKT cells compete for a narrow niche, suggesting that the absence of peptide-MHC on DP thymocytes facilitates selection of non-peptide specific lymphocytes.

References

  1. Edholm, E. S., Banach, M. & Robert, J. Evolution of innate-like T cells and their selection by MHC class I-like molecules. Immunogenetics 68, 525–536 (2016). [PMID: 27368412]
  2. Vermijlen, D. & Prinz, I. Ontogeny of innate T lymphocytes - some innate lymphocytes are more innate than others. Front. Immunol. 5, 1–12 (2014). [DOI: 10.3389/fimmu.2014.00486]
  3. Bendelac, A., Savage, P. B. & Teyton, L. The biology of NKT cells. Annu. Rev. Immunol. 25, 297–336 (2007). [PMID: 17150027]
  4. Stetson, D. B. et al. Constitutive cytokine mRNAs mark natural killer (NK) and NK T cells poised for rapid effector function. J. Exp. Med. 198, 1069–1076 (2003). [PMID: 14530376]
  5. Crowe, N. Y. et al. Glycolipid antigen drives rapid expansion and sustained cytokine production by NK T cells. J. Immunol. 171, 4020–4027 (2003). [PMID: 14530322]
  6. Hayakawa, K., Lin, B. T. & Hardy, R. Murine thymic CD4+ T cell subsets: a subset (Thy0) that secretes diverse cytokines and overexpresses the VB8 T cell receptor gene family. J. Exp. Med. 178, 269–274 (1992). [DOI: 10.1084/jem.176.1.269]
  7. Lantz, O. & Bendelac, A. An invariant T cell receptor ~x chain is used by a unique subset of major histocompatibility complex class I-specific CD4+ and CD4− 8− T cells in mice and humans. J. Exp. Med. 180, 1097–1106 (1994). [PMID: 7520467]
  8. Bendelac, A. Positive selection of mouse NK1+ T cells by CD1-expressing cortical thymocytes. J. Exp. Med. 182, 2091–2096 (1995). [PMID: 7500054]
  9. Benlagha, K., Wei, D. G., Veiga, J., Teyton, L. & Bendelac, A. Characterization of the early stages of thymic NKT cell development. J. Exp. Med. 202, 485–492 (2005). [PMID: 16087715]
  10. Godfrey, D. I., Stankovic, S. & Baxter, A. G. Raising the NKT cell family. Nat. Immunol. 11, 197–206 (2010). [PMID: 20139988]
  11. Kronenberg, M. & Gapin, L. The unconventional lifestyle of NKT cells. Nat. Rev. Immunol. 2, 557–568 (2002). [PMID: 12154375]
  12. Starr, T. K., Jameson, S. C. & Hogquist, K. A. Positive and negative selection of T cells. Annu. Rev. Immunol. 21, 139–176 (2003). [PMID: 12414722]
  13. Griewank, K. et al. Homotypic interactions mediated by Slamf1 and Slamf6 receptors control NKT cell lineage development. Immunity 27, 751–762 (2007). [PMID: 18031695]
  14. Savage, A. K. et al. The transcription factor PLZF directs the effector program of the NKT cell lineage. Immunity 29, 391–403 (2008). [PMID: 18703361]
  15. Kovalovsky, D. et al. The BTB-zinc finger transcriptional regulator PLZF controls the development of invariant natural killer T cell effector functions. Nat. Immunol. 9, 1055–1064 (2008). [PMID: 18660811]
  16. Seach, N. et al. Double positive thymocytes select mucosal-associated invariant T cells. J. Immunol. 191, 6002–6009 (2013). [PMID: 24244014]
  17. Alonzo, E. S. et al. Development of promyelocytic zinc finger and ThPOK-expressing innate γδ T cells is controlled by strength of TCR signaling and Id3. J. Immunol. 184, 1268–1279 (2010). [PMID: 20038637]
  18. Cho, H., Bediako, Y., Xu, H., Choi, H. J. & Wang, C. R. Positive selecting cell type determines the phenotype of MHC class Ib-restricted CD8+ T cells. Proc. Natl Acad. Sci. USA 108, 13241–13246 (2011). [PMID: 21788511]
  19. Xing, Y., Wang, X., Jameson, S. C. & Hogquist, K. A. Late stages of T cell maturation in the thymus involve NF-κB and tonic type i interferon signaling. Nat. Immunol. 17, 565–573 (2016). [PMID: 27043411]
  20. Scollay, R., Jacobs, S., Jerabek, L., Butcher, E. & Weissman, I. T cell maturation: thymocyte and thymus migrant subpopulations defined with monoclonal antibodies to MHC region antigens. J. Immunol. 124, 2845–2853 (1980). [PMID: 6154739]
  21. Eun, Y. C. et al. Thymocyte-thymocyte interaction for efficient positive selection and maturation of CD4 T cells. Immunity 23, 387–396 (2005). [DOI: 10.1016/j.immuni.2005.09.005]
  22. Li, W. et al. An alternate pathway for CD4 T cell development: thymocyte-expressed MHC class II selects a distinct T cell population. Immunity 23, 375–386 (2005). [PMID: 16226503]
  23. Li, W. et al. Thymic selection pathway regulates the effector function of CD4 T cells. J. Exp. Med. 204, 2145–2157 (2007). [PMID: 17724129]
  24. Lee, Y. J. et al. Generation of PLZF+ CD4+ T cells via MHC class II-dependent thymocyte-thymocyte interaction is a physiological process in humans. J. Exp. Med. 207, 237–246 (2010). [PMID: 20038602]
  25. Meissner, T. B. et al. NLR family member NLRC5 is a transcriptional regulator of MHC class I genes. Proc. Natl Acad. Sci. USA 107, 13794–13799 (2010). [PMID: 20639463]
  26. Meissner, T. B., Li, A. & Kobayashi, K. S. NLRC5: a newly discovered MHC class I transactivator (CITA). Microbes Infect. 14, 477–484 (2012). [PMID: 22209772]
  27. Jongsma, M. L. M., Guarda, G. & Spaapen, R. M. The regulatory network behind MHC class I expression. Mol. Immunol. 113, 16–21 (2019). [PMID: 29224918]
  28. Biswas, A., Meissner, T. B., Kawai, T. & Kobayashi, K. S. Cutting edge: impaired MHC class I expression in mice deficient for Nlrc5/class I transactivator. J. Immunol. 189, 516–520 (2012). [PMID: 22711889]
  29. Lee, Y. J., Jung, K. C. & Park, S. H. MHC class II-dependent T-T interactions create a diverse, functional and immunoregulatory reaction circle. Immunol. Cell Biol. 87, 65–71 (2009). [PMID: 19030015]
  30. Heng, T. S. P. et al. The Immunological Genome Project: networks of gene expression in immune cells. Nat. Immunol. 9, 1091–1094 (2008). [PMID: 18800157]
  31. Min, H. S. et al. MHC class II-restricted interaction between thymocytes plays an essential role in the production of innate CD8 + T cells. J. Immunol. 186, 5749–5757 (2011). [PMID: 21478404]
  32. Lee, Y. J., Holzapfel, K. L., Zhu, J., Jameson, S. C. & Hogquist, K. A. Steady-state production of IL-4 modulates immunity in mouse strains and is determined by lineage diversity of iNKT cells. Nat. Immunol. 14, 1146–1154 (2013). [PMID: 24097110]
  33. Georgiev, H., Ravens, I., Benarafa, C., Förster, R. & Bernhardt, G. Distinct gene expression patterns correlate with developmental and functional traits of iNKT subsets. Nat. Commun. 7, 13116 (2016). [PMID: 27721447]
  34. Engel, I. et al. Innate-like functions of natural killer T cell subsets result from highly divergent gene programs. Nat. Immunol. 17, 728–739 (2016). [PMID: 27089380]
  35. Lee, Y. J. et al. Lineage-specific effector signatures of invariant NKT cells are shared amongst γδ T, innate lymphoid, and Th cells. J. Immunol. 197, 1460–1470 (2016). [PMID: 27385777]
  36. Tuttle, K. D. et al. TCR signal strength controls thymic differentiation of iNKT cell subsets. Nat. Commun. 9, 2650 (2018). [PMID: 29985393]
  37. Hogquist, K. & Georgiev, H. Recent advances in iNKT cell development. F1000Research 9, 127 (2020). [DOI: 10.12688/f1000research.21378.1]
  38. Krovi, S. H. & Gapin, L. Invariant natural killer T cell subsets—more than just developmental intermediates. Front. Immunol. 9, 1393 (2018). [PMID: 29973936]
  39. Zhao, M. et al. Altered thymic differentiation and modulation of arthritis by invariant NKT cells expressing mutant ZAP70. Nat. Commun. 9, 2627 (2018). [PMID: 29980684]
  40. Benlagha, K., Kyin, T., Beavis, A., Teyton, L. & Bendelac, A. A thymic precursor to the NK T cell lineage. Science 296, 553–555 (2002). [PMID: 11968185]
  41. Lee, Y. J., Jameson, S. C. & Hogquist, K. A. Alternative memory in the CD8 T cell lineage. Trends Immunol. 32, 50–56 (2011). [PMID: 21288770]
  42. Erman, B. et al. Coreceptor signal strength regulates positive selection but does not determine CD4/CD8 lineage choice in a physiologic in vivo model. J. Immunol. 177, 6613–6625 (2006). [PMID: 17082573]
  43. Li, W. et al. MHC class II-expressing thymocytes suppress invariant NKT cell development. Immunol. Cell Biol. 87, 186–189 (2009). [PMID: 18982019]
  44. Georgiev, H., Ravens, I., Shibuya, A., Förster, R. & Bernhardt, G. CD155/CD226-interaction impacts on the generation of innate CD8(+) thymocytes by regulating iNKT-cell differentiation. Eur. J. Immunol. 46, 993–1003 (2016). [PMID: 26689152]
  45. Kang, B. H. et al. Analyses of the TCR repertoire of MHC class II-restricted innate CD4+ T cells. Exp. Mol. Med. 47, e154 (2015). [PMID: 25813222]
  46. Kurepa, Z., Su, J. & Forman, J. Memory phenotype of CD8+ T cells in MHC class Ia-deficient mice. J. Immunol. 170, 5414–5420 (2003). [PMID: 12759416]
  47. Bediako, Y. et al. SAP is required for the devof innate phenotype in H2-M3–restricted CD8+ T cells. J. Immunol. 189, 4787–4796 (2012). [PMID: 23041566]
  48. Bendelac, A., Killeen, N., Littman, D. R. & Schwartz, R. H. A subset of CD4+ thymocytes selected by MHC class I molecules. Science 263, 1774–1778 (1994). [PMID: 7907820]
  49. Engel, I. et al. Co-receptor choice by Vα14i NKT cells is driven by Th-POK expression rather than avoidance of CD8-mediated negative selection. J. Exp. Med. 207, 1015–1029 (2010). [PMID: 20404101]
  50. Dashtsoodol, N., Bortoluzzi, S. & Schmidt-Supprian, M. T cell receptor expression timing and signal strength in the functional differentiation of invariant natural killer T cells. Front. Immunol. 10, 841 (2019). [PMID: 31080448]
  51. Wiest, D. L. et al. Regulation of T cell receptor expression in immature CD4+CD8+ thymocytes by p56lck tyrosine kinase: basis for differential signaling by CD4 and CD8 in immature thymocytes expressing both coreceptor molecules. J. Exp. Med. 178, 1701–1712 (1993). [PMID: 8228817]
  52. Wiest, D. L., Ashe, J. M., Ryo, A., Bolen, J. B. & Singer, A. TCR activation of ZAP70 is impaired in CD4+CD8+ thymocytes as a consequence of intrathymic interactions that diminish available P56(lck). Immunity 4, 495–504 (1996). [PMID: 8630734]
  53. Germain, R. N. T-cell development and the CD4-CD8 lineage decision. Nat. Rev. Immunol. 2, 309–322 (2002). [PMID: 12033737]
  54. Benko, S., Kovács, E. G., Hezel, F. & Kufer, T. A. NLRC5 functions beyond MHC I regulation-What do we know so far? Front. Immunol. 8, 1–7 (2017). [DOI: 10.3389/fimmu.2017.00150]
  55. Wang, J. Q. et al. Emerging roles for NLRC5 in immune diseases. Front. Pharm. 10, 1–13 (2019). [DOI: 10.3389/fphar.2019.01352]
  56. Cui, J. et al. NLRC5 Negatively regulates the NF-κB and type I interferon signaling pathways. Cell 141, 483–496 (2010). [PMID: 20434986]
  57. Meng, Q. et al. Reversible ubiquitination shapes NLRC5 function and modulates NF-κB activation switch. J. Cell Biol. 211, 1025–1040 (2015). [PMID: 26620909]
  58. Tong, Y. et al. Enhanced TLR-induced NF-κB signaling and type I interferon responses in NLRC5 deficient mice. Cell Res. 22, 822–835 (2012). [PMID: 22473004]
  59. Long, M., Park, S. G., Strickland, I., Hayden, M. S. & Ghosh, S. Nuclear factor-κB modulates regulatory T cell development by directly regulating expression of Foxp3 transcription factor. Immunity 31, 921–931 (2009). [PMID: 20064449]
  60. Isomura, I. et al. c-Rel is required for the development of thymic Foxp3+ CD4 regulatory T cells. J. Exp. Med. 206, 3001–3014 (2009). [PMID: 19995950]
  61. Gordy, L. E. et al. IL-15 regulates homeostasis and terminal maturation of NKT cells. J. Immunol. 187, 6335–6345 (2011). [PMID: 22084435]
  62. Miller, C. N. et al. Thymic tuft cells promote an IL-4-enriched medulla and shape thymocyte development. Nature 559, 627–631 (2018). [PMID: 30022164]
  63. Matsuda, J. L. et al. Homeostasis of Vα14i NKT cells. Nat. Immunol. 3, 966–974 (2002). [PMID: 12244311]
  64. Wang, H., Hogquist, K. A. & How Lipid-Specific, T. Cells become effectors: the differentiation of iNKT subsets. Front. Immunol. 9, 1450 (2018). [PMID: 29997620]
  65. Tiscornia, G., Singer, O. & Verma, I. M. Production and purification of lentiviral vectors. Nat. Protoc. 1, 241–245 (2006). [PMID: 17406239]

Grants

  1. R37 AI039560/NIAID NIH HHS

MeSH Term

Animals
Cell Differentiation
Histocompatibility Antigens Class I
Immunity, Innate
Intracellular Signaling Peptides and Proteins
Mice
Mice, Transgenic
Mucosal-Associated Invariant T Cells
Natural Killer T-Cells
Promyelocytic Leukemia Zinc Finger Protein
Thymocytes
Thymus Gland

Chemicals

Histocompatibility Antigens Class I
Intracellular Signaling Peptides and Proteins
NLRC5 protein, mouse
Promyelocytic Leukemia Zinc Finger Protein
Zbtb16 protein, mouse
Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't
Article has an altmetric score of 1

Word Cloud

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