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

Abstract

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.

Figure 1

Conceptual model of dual and biphasic roles of Tregs in SARS-CoV-2 infection and immunopathology of COVID-19. In SARS-CoV-2 infection, Tregs are likely to play detrimental and beneficial dual roles and biphasic roles in the early and late stages of the disease. (A) The augmented Treg population in the early stage of infection potently suppresses the mobilization of host defensive immune cells such as Th1 cells and CD8⁺ CTLs, consequently reducing anti-viral immune responses. (B) An increased number of Tregs could attenuate the inflammatory responses and quench the cytokine storm; this can promote the recovery of patients. (C) In severe COVID-19, depletion of Tregs can enhance the activation of pro-inflammatory immune cells and production of pro-inflammatory cytokines that cause cytokine storm and lead to lung injury, ARDS, and eventually the death of patients.

Figure 2

Comparison of Treg-targeted treatments for COVID-19. Adoptive transfer of ex vivo activated and expanded allogeneic cord-blood derived Tregs and low-dose of recombinant interleukin-2 (rIL-2) enhance Treg activity in severe COVID-19 patients, consequently, dampen the excessive inflammation and quench cytokine storm.