The Dynamic Role of FOXP3+ Tregs and Their Potential Therapeutic Applications During SARS-CoV-2 Infection

Abstract

Coronavirus disease 2019 (COVID-19) has been raging all around the world since the beginning of 2020, and leads to acute respiratory distress syndrome (ARDS) with strong cytokine storm which contributes to widespread tissue damage and even death in severe patients. Over-activated immune response becomes one of the characteristics of severe COVID-19 patients. Regulatory T cells (Treg) play an essential role in maintaining the immune homeostasis, which restrain excessive inflammation response. So FOXP3⁺ Tregs might participate in the suppression of inflammation caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Besides suppressive function, tissue resident Tregs are also responsible for tissue repair. In this review, we mainly summarize the latest research focusing on the change of FOXP3⁺ Tregs in the COVID-19 patients, discuss the relationship between disease severity and number change of Tregs and speculate the potential role of FOXP3⁺ Tregs during SARS-CoV-2 infection. Furthermore, we introduce some potential Treg-based therapies to improve patients' outcomes, which include small molecular drugs, antibody drugs, CAR-Treg and cytokine treatment. We hope to reduce tissue damage of severe COVID-19 patients and offer better prognosis through Treg-based therapy.

Keywords: COVID-19; FOXP3; SARS-CoV-2; Treg; Treg-based therapy.

Figure 1

Treg suppressive mechanisms.Treg could secrete immunosuppressive cytokines including IL-10, TGF-β, and IL-35. In addition, Treg could induce cytolysis by Granzyme-dependent and Perforin-dependent mechanisms. The CD25 on Treg competitively binds to IL-2 and mediates apoptosis of effector immune cells through cytokine-deprivation. The interaction of LAG-3 and MHC-II mediates suppression of DC maturation, the interaction of CTLA-4 and CD80/86 mediates the production of immunosuppressive molecule IDO in DC. CD39 and CD73 facilitate the generation of pericellular adenosine, whose suppressive function is mediated through A_2AR. Treg inhibits B cell activity via the interaction of PD-L1/2 and PD-1.

Figure 2

Lung resident Treg plays protective role under acute lung injury. Besides suppressing the excessive inflammatory response and keeping immune tolerance under the condition of acute lung injury, lung resident Tregs also produce Amphiregulin under the stimulation of IL-18 or alarmin IL-33 during lung injury by viral infection. Amphiregulin is crucial for Treg cell-mediated tissue repair.

Figure 3

Treg has dual roles during SARS-CoV-2 infection. The balance between Treg suppressive function for maintaining immune homeostasis and antiviral immune responses for eliminating SARS-CoV-2 is proposed to be kept well in the mild patients. When this balance is broken, patients will suffer poorer prognosis. Excessive Treg activity will result in virus persistence, more production of pro-inflammatory DAMPs and PAMPs and exacerbated inflammation. Insufficient Treg activity will contribute to aggressive inflammatory response with cytokine storm which leads to tissue damage and ARDS. More researches are required to explore the best time for Treg-based therapy to avoid severe COVID-19 symptom.