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The transcription factor RelB restrains group 2 innate lymphoid cells and type 2 immune pathology in vivo

Cellular & Molecular Immunology volume 18, pages 230–242 (2021)Cite this article

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Abstract

The exact relationships between group 2 innate lymphoid cells (ILC2s) and Th2 cells in type 2 pathology, as well as the mechanisms that restrain the responses of these cells, remain poorly defined. Here we examined the roles of ILC2s and Th2 cells in type 2 lung pathology in vivo using germline and conditional Relb-deficient mice. We found that mice with germline deletion of Relb (Relb−/−) spontaneously developed prominent type 2 pathology in the lung, which contrasted sharply with mice with T-cell-specific Relb deletion (Relbf/fCd4-Cre), which were healthy with no observed autoimmune pathology. We also found that in contrast to wild-type B6 mice, Relb-deficient mice showed markedly expanded ILC2s but not ILC1s or ILC3s. Moreover, adoptive transfer of naive CD4+ T cells into Rag1−/−Relb−/− hosts induced prominent type 2 lung pathology, which was inhibited by depletion of ILC2s. Mechanistically, we showed that Relb deletion led to enhanced expression of Bcl11b, a key transcription factor for ILC2s. We concluded that RelB plays a critical role in restraining ILC2s, primarily by suppressing Bcl11b activity, and consequently inhibits type 2 lung pathology in vivo.

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References

  1. Nakayama, T. et al. Th2 cells in health and disease. Annu. Rev. Immunol. 35, 53–84 (2017).

    CAS  PubMed  Google Scholar 

  2. Muehling, L. M., Lawrence, M. G. & Woodfolk, J. A. Pathogenic CD4(+) T cells in patients with asthma. J. Allergy Clin. Immunol. 140, 1523–1540 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Winkler, C. et al. Activation of group 2 innate lymphoid cells after allergen challenge in asthmatic patients. J. Allergy Clin. Immunol. 144, 61–69 (2019). e67.

    CAS  PubMed  Google Scholar 

  5. Zook, E. C. & Kee, B. L. Development of innate lymphoid cells. Nat. Immunol. 17, 775–782 (2016).

    CAS  PubMed  Google Scholar 

  6. Panda, S. K. & Colonna, M. Innate lymphoid cells in mucosal immunity. Front Immunol. 10, 861 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Schneider, C. et al. Tissue-resident group 2 innate lymphoid cells differentiate by layered ontogeny and in situ perinatal priming. Immunity 50, 1425–1438 (2019). e1425.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Vivier, E., van de Pavert, S. A., Cooper, M. D. & Belz, G. T. The evolution of innate lymphoid cells. Nat. Immunol. 17, 790–794 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Deckers, J., Branco Madeira, F. & Hammad, H. Innate immune cells in asthma. Trends Immunol. 34, 540–547 (2013).

    CAS  PubMed  Google Scholar 

  10. Vivier, E. et al. Innate lymphoid cells: 10 years on. Cell 174, 1054–1066 (2018).

    CAS  PubMed  Google Scholar 

  11. Kubo, M. Innate and adaptive type 2 immunity in lung allergic inflammation. Immunol. Rev. 278, 162–172 (2017).

    CAS  PubMed  Google Scholar 

  12. Germain, R. N. & Huang, Y. ILC2s - resident lymphocytes pre-adapted to a specific tissue or migratory effectors that adapt to where they move? Curr. Opin. Immunol. 56, 76–81 (2019).

    CAS  PubMed  Google Scholar 

  13. Drake, L. Y. & Kita, H. Group 2 innate lymphoid cells in the lung. Adv. Immunol. 124, 1–16 (2014).

    PubMed  PubMed Central  Google Scholar 

  14. Lanier, L. L. Shades of grey–the blurring view of innate and adaptive immunity. Nat. Rev. Immunol. 13, 73–74 (2013).

    CAS  PubMed  Google Scholar 

  15. Gurram, R. K. & Zhu, J. Orchestration between ILC2s and Th2 cells in shaping type 2 immune responses. Cell Mol. Immunol. 16, 225–235 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhu, J. T helper 2 (Th2) cell differentiation, type 2 innate lymphoid cell (ILC2) development and regulation of interleukin-4 (IL-4) and IL-13 production. Cytokine 75, 14–24 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Califano, D. et al. Transcription factor Bcl11b controls identity and function of mature type 2 innate lymphoid cells. Immunity 43, 354–368 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Wu, J. et al. Ablation of transcription factor IRF4 promotes transplant acceptance by driving allogenic CD4(+) T cell dysfunction. Immunity 47, 1114–1128 (2017). e1116.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Li, J. et al. Role of the NF-kappaB family member RelB in regulation of Foxp3(+) regulatory T cells in vivo. J. Immunol. 200, 1325–1334 (2018).

    CAS  PubMed  Google Scholar 

  20. Xiao, X. et al. The costimulatory receptor OX40 inhibits interleukin-17 expression through activation of repressive chromatin remodeling pathways. Immunity 44, 1271–1283 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. McHedlidze, T. et al. Interleukin-33-dependent innate lymphoid cells mediate hepatic fibrosis. Immunity 39, 357–371 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Ma, Y. et al. Sustained suppression of IL-13 by a vaccine attenuates airway inflammation and remodeling in mice. Am. J. Respir. Cell Mol. Biol. 48, 540–549 (2013).

    CAS  PubMed  Google Scholar 

  23. Xiao, X. et al. OX40 signaling favors the induction of T(H)9 cells and airway inflammation. Nat. Immunol. 13, 981–990 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Weih, F. et al. Both multiorgan inflammation and myeloid hyperplasia in RelB-deficient mice are T cell dependent. J. Immunol. 157, 3974–3979 (1996).

    CAS  PubMed  Google Scholar 

  25. Zhang, L., Xiao, X., Arnold, P. R. & Li, X. C. Transcriptional and epigenetic regulation of immune tolerance: roles of the NF-kappaB family members. Cell Mol. Immunol. 16, 315–323 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Sun, S. C. The noncanonical NF-kappaB pathway. Immunol. Rev. 246, 125–140 (2012).

    PubMed  PubMed Central  Google Scholar 

  27. Jin, C. & Zhu, M. RelB intrinsically regulates the development and function of medullary thymic epithelial cells. Sci. China Life Sci. 61, 1039–1048 (2018).

    CAS  PubMed  Google Scholar 

  28. Weih, F. et al. Multiorgan inflammation and hematopoietic abnormalities in mice with a targeted disruption of RelB, a member of the NF-kappa B/Rel family. Cell 80, 331–340 (1995).

    CAS  PubMed  Google Scholar 

  29. Riemann, M. et al. Central immune tolerance depends on crosstalk between the classical and alternative NF-kappaB pathways in medullary thymic epithelial cells. J. Autoimmun. 81, 56–67 (2017).

    CAS  PubMed  Google Scholar 

  30. Diefenbach, A., Colonna, M. & Koyasu, S. Development, differentiation, and diversity of innate lymphoid cells. Immunity 41, 354–365 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Yu, Y. et al. The transcription factor Bcl11b is specifically expressed in group 2 innate lymphoid cells and is essential for their development. J. Exp. Med. 212, 865–874 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Walker, J. A. et al. Bcl11b is essential for group 2 innate lymphoid cell development. J. Exp. Med 212, 875–882 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Sonnenberg, G. F. & Hepworth, M. R. Functional interactions between innate lymphoid cells and adaptive immunity. Nat. Rev. Immunol. 19, 599–613 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Serafini, N., Vosshenrich, C. A. & Di Santo, J. P. Transcriptional regulation of innate lymphoid cell fate. Nat. Rev. Immunol. 15, 415–428 (2015).

    CAS  PubMed  Google Scholar 

  35. Zhang, Q., Lenardo, M. J. & Baltimore, D. 30 Years of NF-kappaB: a blossoming of relevance to human pathobiology. Cell 168, 37–57 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Martinez-Gonzalez, I., Steer, C. A. & Takei, F. Lung ILC2s link innate and adaptive responses in allergic inflammation. Trends Immunol. 36, 189–195 (2015).

    CAS  PubMed  Google Scholar 

  37. Nair, P. M. et al. RelB-deficient dendritic cells promote the development of spontaneous allergic airway inflammation. Am. J. Respir. Cell Mol. Biol. 58, 352–365 (2018).

    CAS  PubMed  Google Scholar 

  38. Roediger, B. et al. IL-2 is a critical regulator of group 2 innate lymphoid cell function during pulmonary inflammation. J. Allergy Clin. Immunol. 136, 1653–1663 (2015). e1657.

    CAS  PubMed  Google Scholar 

  39. Constantinides, M. G., McDonald, B. D., Verhoef, P. A. & Bendelac, A. A committed precursor to innate lymphoid cells. Nature 508, 397–401 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Ishizuka, I. E., Constantinides, M. G., Gudjonson, H. & Bendelac, A. The innate lymphoid cell precursor. Annu Rev. Immunol. 34, 299–316 (2016).

    CAS  PubMed  Google Scholar 

  41. Walker, J. A. et al. Polychromic reporter mice reveal unappreciated innate lymphoid cell progenitor heterogeneity and elusive ILC3 progenitors in bone marrow. Immunity 51, 104–118 (2019). e107.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We acknowledge the Flow Cytometry Core and the Pathology Core at Houston Methodist for excellent services. This work was supported in part by the National Institutes of Health (R01AI080779) and the Kleberg Foundation.

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Authors and Affiliations

  1. Immunobiology and Transplant Science Center, and Department of Surgery, Houston Methodist Hospital, Texas Medical Center, Houston, Texas, USA

    Lei Zhang, Yuanlin Ying, Shuqiu Chen, Preston R. Arnold, Xiang Xiao & Xian C. Li

  2. Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

    Lei Zhang & Fafa Tian

  3. Department of Urology, Southeast University Zhongda Hospital, Nanjing, China

    Shuqiu Chen

  4. Department of Surgery, Weill Cornell Medical College of Cornell University, New York, NY, USA

    Xian C. Li

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  1. Lei Zhang
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Correspondence to Xian C. Li.

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Zhang, L., Ying, Y., Chen, S. et al. The transcription factor RelB restrains group 2 innate lymphoid cells and type 2 immune pathology in vivo. Cell Mol Immunol 18, 230–242 (2021). https://doi.org/10.1038/s41423-020-0404-0

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