The role of CD4 + FoxP3 + regulatory T cells in the immunopathogenesis of COVID-19: implications for treatment

Int J Biol Sci. 2021 Apr 10;17(6):1507-1520. doi: 10.7150/ijbs.59534. eCollection 2021.


The severe cases of Coronavirus Disease 2019 (COVID-19) frequently exhibit excessive inflammatory responses, acute respiratory distress syndrome (ARDS), coagulopathy, and organ damage. The most striking immunopathology of advanced COVID-19 is cytokine release syndrome or "cytokine storm" that is attributable to the deficiencies in immune regulatory mechanisms. CD4+FoxP3+ regulatory T cells (Tregs) are central regulators of immune responses and play an indispensable role in the maintenance of immune homeostasis. Tregs are likely involved in the attenuation of antiviral defense at the early stage of infection and ameliorating inflammation-induced organ injury at the late stage of COVID-19. In this article, we review and summarize the current understanding of the change of Tregs in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and discuss the potential role of Tregs in the immunopathology of COVID-19. The emerging concept of Treg-targeted therapies, including both adoptive Treg transfer and low dose of IL-2 treatment, is introduced. Furthermore, the potential Treg-boosting effect of therapeutic agents used in the treatment of COVID-19, including dexamethasone, vitamin D, tocilizumab and sarilumab, chloroquine, hydroxychloroquine, azithromycin, adalimumab and tetrandrine, is discussed. The problems in the current study of Treg cells in COVID-19 and future perspectives are also addressed.

Keywords: CD4+FoxP3+ regulatory T cells; COVID-19; SARS-CoV-2; immunopathology.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • CD4 Antigens / immunology*
  • COVID-19 / immunology*
  • COVID-19 / therapy*
  • COVID-19 / virology
  • Cytokine Release Syndrome
  • Forkhead Transcription Factors / immunology*
  • Humans
  • SARS-CoV-2 / isolation & purification
  • T-Lymphocytes, Regulatory / immunology*


  • CD4 Antigens
  • FOXP3 protein, human
  • Forkhead Transcription Factors