Regulatory T Cells as Predictors of Clinical Course in Hospitalised COVID-19 Patients

Abstract

BackgroundThe host immune response has a prominent role in the progression and outcome of SARS-CoV-2 infection. Lymphopenia has been described as an important feature of SARS-CoV-2 infection and has been associated with severe disease manifestation. Lymphocyte dysregulation and hyper-inflammation have been shown to be associated with a more severe clinical course; however, a T cell subpopulation whose dysfunction correlate with disease progression has yet to be identify.MethodsWe performed an immuno-phenotypic analysis of T cell sub-populations in peripheral blood from patients affected by different severity of COVID-19 (n=60) and undergoing a different clinical evolution. Clinical severity was established based on a modified WHO score considering both ventilation support and respiratory capacity (PaO2/FiO2 ratio). The ability of circulating cells at baseline to predict the probability of clinical aggravation was explored through multivariate regression analyses.ResultsThe immuno-phenotypic analysis performed by multi-colour flow cytometry confirmed that patients suffering from severe COVID-19 harboured significantly reduced circulating T cell subsets, especially for CD4+ T, Th1, and regulatory T cells. Peripheral T cells also correlated with parameters associated with disease severity, i.e., PaO2/FiO2 ratio and inflammation markers. CD4+ T cell subsets showed an important significant association with clinical evolution, with patients presenting markedly decreased regulatory T cells at baseline having a significantly higher risk of aggravation. Importantly, the combination of gender and regulatory T cells allowed distinguishing between improved and worsened patients with an area under the ROC curve (AUC) of 82%.ConclusionsThe present study demonstrates the association between CD4+ T cell dysregulation and COVID-19 severity and progression. Our results support the importance of analysing baseline regulatory T cell levels, since they were revealed able to predict the clinical worsening during hospitalization. Regulatory T cells assessment soon after hospital admission could thus allow a better clinical stratification and patient management.

A scoping review of regulatory T cell dynamics in convalescent COVID-19 patients – Implications for Long COVID?

“…Earlier studies investigating patients during acute illness revealed that COVID-19 can induce alterations in lymphocyte frequency and functioning that are associated with disease severity and prognosis (2,40,(67)(68)(69). In severe cases, a loss of CD4 + lymphocytes, including Tregs is a prominent clinical feature that, together with an enhanced myelopoiesis, contributes to an expansion of neutrophils, dendritic cells and macrophages, favoring immunopathology, excessive tissue infiltration and acute respiratory distress syndrome (40,41,(70)(71)(72)(73). Of note, the decrease of Tregs in severe COVID-19 patients is not only a reflection of diminished absolute cell counts in the context of lymphopenia but is also linked to altered relative cell frequencies, as a result of Th17 cell expansion (74).…”

“…Nevertheless, a trend toward functional impairments and decreased levels of circulating Tregs in severe cases of COVID-19 has been reported previously (33–35). It was shown that patients dying from COVID-19 exhibited significantly lower Treg counts and higher Th17/Treg ratio compared to recovered and healthy controls (37–39) and that low Treg counts at hospital admission were associated with clinical worsening and longer duration to discharge (40, 41). Correspondingly, several studies demonstrated a downregulation of FoxP3 in severe cases of COVID-19 (39, 42–44).…”

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

“…Moreover, a single-cell transcriptomic analysis of viral antigen-reactive CD4 + T cells from 40 COVID-19 patients got the conclusion that SARS-CoV-2-reactive Tregs were dramatically reduced in hospitalized COVID-19 patients, while the proportions of cytotoxic follicular helper cells and cytotoxic T helper cells responding to SARS-CoV-2 were increased (80). Other study highlighted that, compared to mild or moderate subjects, the absolute number of total lymphocytes of severe COVID-19 patients was reduced and the amount of Tregs was negatively correlated to viral load, suggesting reduced Tregs stood for increased risk of worsening during the hospitalization (81). A study in Wuhan showed severe COVID-19 patients presented decreased regulatory T cells (CD3 + CD4 + CD25 + CD127 low ) proportion (82).…”

The Potential of Purinergic Signaling to Thwart Viruses Including SARS-CoV-2

“…The interleukin twelve (IL-12)-induced Th1 subset generates interferon gamma (IFN-g) and tumor necrosis factor (TNF-a) whereas the IL-6 driven Th17 cells generate IL-17 and IL-21 (165). Recent studies have shown significant reduction of T regs in COVID-19 patients, with an imbalance in the Treg/Th17 ratio weakening inflammatory inhibition worsening patient prognosis (166).…”