Immunologic Research

, Volume 66, Issue 2, pp 281–287 | Cite as

CD27+TIM-1+ memory B cells promoted the development of Foxp3+ Tregs and were associated with better survival in acute respiratory distress syndrome

  • Guangfa Zhu
  • Yan Liu
  • Wenmei Zhang
  • Yan Huang
  • Keng Li
Original Article


Acute respiratory distress syndrome (ARDS) is a rapid onset life-threatening condition involving uncontrolled propagation of inflammatory responses. Here, we observed that ARDS patients that survived presented significantly higher frequencies of TIM-1+ B cells, especially the CD27+TIM-1+ B cells, than the ARDS patients who succumbed to the condition. We then found that using BCR/CD40 antigen-dependent stimulation or Staphylococcus aureus Cowan (SAC) antigen-independent stimulation, TIM-1+ B cells presented significantly higher IL-10 secretion and/or TGF-β1 secretion, with SAC stimulation being more effective. CD4+ T cells that incubated with TIM-1+ B cells presented significantly elevated IL-10 secretion, TGF-β1 secretion, and Foxp3 expression, than CD4+ T cells that incubated with TIM-1 B cells, suggesting TIM-1+ B cells promoted the in vitro development of Foxp3+ Treg cells. Interestingly, this TIM-1+ B cell-mediated promotion of Foxp3 expression was mostly dependent on TGF-β1 but not IL-10, since neutralization of TGF-β1, but not IL-10, resulted in the suppression of Foxp3 expression. We further showed that in TIM-1+ B cells, the CD27+ classical memory B cell subset demonstrated more regulatory potency than the CD27 subset. Together, our results suggested that the TIM-1+ B cells, especially those that expressed CD27, could promote Foxp3 expression. Their clinical efficacy in treating ARDS should be examined in in vivo experiments.


TIM-1+ B cell Breg IL-10 ALI 


Compliance with ethical standards

Following ethical approval by Anzhen Hospital ethics committee and receiving written informed consent, peripheral blood was collected form the patients after admission into the intensive care units.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Umetsu SE, Lee W-L, McIntire JJ, Downey L, Sanjanwala B, Akbari O, et al. TIM-1 induces T cell activation and inhibits the development of peripheral tolerance. Nat Immunol. 2005;6(5):447–54. Scholar
  2. 2.
    Ding Q, Yeung M, Camirand G, Zeng Q, Akiba H, Yagita H, et al. Regulatory B cells are identified by expression of TIM-1 and can be induced through TIM-1 ligation to promote tolerance in mice. J Clin Invest. 2011;121(9):3645–56. Scholar
  3. 3.
    Xiao S, Brooks CR, Zhu C, Wu C, Sweere JM, Petecka S, et al. Defect in regulatory B-cell function and development of systemic autoimmunity in T-cell Ig mucin 1 (Tim-1) mucin domain-mutant mice. Proc Natl Acad Sci. 2012;10:12105–10.CrossRefGoogle Scholar
  4. 4.
    Yeung MY, Ding Q, Brooks CR, Xiao S, Workman CJ, Vignali DAA, et al. TIM-1 signaling is required for maintenance and induction of regulatory B cells. Am J Transplant. 2015;15(4):942–53. Scholar
  5. 5.
    Xiao S, Brooks CR, Sobel RA, Kuchroo VK. Tim-1 is essential for induction and maintenance of IL-10 in regulatory B cells and their regulation of tissue inflammation. J Immunol. 2015;194(4):1602–8. Scholar
  6. 6.
    Aravena O, Ferrier A, Menon M, Mauri C, Aguillón JC, Soto L, et al. TIM-1 defines a human regulatory B cell population that is altered in frequency and function in systemic sclerosis patients. Arthritis Res Ther. 2017;19(1):8. Scholar
  7. 7.
    Liu J, Zhan W, Kim CJ, Clayton K, Zhao H, Lee E, Cao JC, Ziegler B, Gregor A, Yue FY, Huibner S, MacParland S, Schwartz J, Song HH, Benko E, Gyenes G, Kovacs C, Kaul R, Ostrowski M IL-10-producing B cells are induced early in HIV-1 infection and suppress HIV-1-specific T cell responses. Unutmaz D, editor. PLoS One 2014;9:e89236, 2, DOI:
  8. 8.
    Donahoe M. Acute respiratory distress syndrome: a clinical review. Pulm Circ. 2011;1(2):192–211. Scholar
  9. 9.
    Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, et al. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA. 2016;315(8):788–800. Scholar
  10. 10.
    Matthay MA, Zimmerman GA. Acute lung injury and the acute respiratory distress syndrome: four decades of inquiry into pathogenesis and rational management. Am J Respir Cell Mol Biol. 2005;33(4):319–27. Scholar
  11. 11.
    Garibaldi BT, D’Alessio FR, Mock JR, Files DC, Chau E, Eto Y, et al. Regulatory T cells reduce acute lung injury fibroproliferation by decreasing fibrocyte recruitment. Am J Respir Cell Mol Biol. 2013;48(1):35–43. Scholar
  12. 12.
    Singer BD, Mock JR, Aggarwal NR, Garibaldi BT, Sidhaye VK, Florez MA, et al. Regulatory T cell DNA methyltransferase inhibition accelerates resolution of lung inflammation. Am J Respir Cell Mol Biol. 2015;52(5):641–52. Scholar
  13. 13.
    D’Alessio FR, Tsushima K, Aggarwal NR, West EE, Willett MH, Britos MF, et al. CD4+CD25+Foxp3+ Tregs resolve experimental lung injury in mice and are present in humans with acute lung injury. J Clin Invest. 2009;119(10):2898–913. Scholar
  14. 14.
    Song H, Zhou Y, Li G, Bai J, Regulatory T. Cells contribute to the recovery of acute lung injury by upregulating Tim-3. Inflammation. 2015;38(3):1267–72. Scholar
  15. 15.
    Li H-D, Zhang Q-X, Mao Z, X-J X, Li N-Y, Zhang H. Exogenous interleukin-10 attenuates hyperoxia-induced acute lung injury in mice. Exp Physiol. 2015;100(3):331–40. Scholar
  16. 16.
    Villar J, Pérez-Méndez L, Kacmarek RM. Current definitions of acute lung injury and the acute respiratory distress syndrome do not reflect their true severity and outcome. Intensive Care Med. 1999;25(9):930–5. Scholar
  17. 17.
    Lee KM, Stott RT, Zhao G, SooHoo J, Xiong W, Lian MM, et al. TGF-β-producing regulatory B cells induce regulatory T cells and promote transplantation tolerance. Eur J Immunol. 2014;44(6):1728–36. Scholar
  18. 18.
    Wang WW, Yuan XL, Chen H, Xie GH, Ma YH, Zheng YX, et al. CD19+CD24hiCD38hiBregs involved in downregulate helper T cells and upregulate regulatory T cells in gastric cancer. Oncotarget. 2015;6(32):33486–99. Scholar
  19. 19.
    Mauri C, Menon M. The expanding family of regulatory B cells. Int Immunol. 2015;27(10):479–86. Scholar
  20. 20.
    Iwata Y, Matsushita T, Horikawa M, DiLillo DJ, Yanaba K, Venturi GM, et al. Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells. Blood. 2011;117(2):530–41. Scholar
  21. 21.
    Blair PA, Noreña LY, Flores-Borja F, Rawlings DJ, Isenberg DA, Ehrenstein MR, et al. CD19(+)CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic lupus erythematosus patients. Immunity. 2010;32(1):129–40. Scholar
  22. 22.
    Shen P, Roch T, Lampropoulou V, O’Connor RA, Stervbo U, Hilgenberg E, et al. IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases. Nature. 2014;507(7492):366–70. Scholar
  23. 23.
    Tedder TF, Leonard WJ. Autoimmunity: regulatory B cells—IL-35 and IL-21 regulate the regulators. Nat Rev Rheumatol. 2014;10(8):452–3. Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Guangfa Zhu
    • 1
    • 2
  • Yan Liu
    • 2
  • Wenmei Zhang
    • 1
  • Yan Huang
    • 1
  • Keng Li
    • 2
  1. 1.Department of Pulmonary and Critical Care Medicine, Beijing Anzhen Hospital, Beijing Institute of Heart, Lung and Blood Vessel DiseasesCapital Medical UniversityBeijingPeople’s Republic of China
  2. 2.Department of Infectious Diseases, Beijing Anzhen Hospital, Beijing Institute of Heart, Lung and Blood Vessel DiseasesCapital Medical UniversityBeijingPeople’s Republic of China

Personalised recommendations