Accumulation of CD28null Senescent T-Cells Is Associated with Poorer Outcomes in COVID19 Patients

Abstract

Coronavirus disease 2019 (COVID-19), a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes infectious disease, and manifests in a wide range of symptoms from asymptomatic to severe illness and even death. Severity of infection is related to many risk factors, including aging and an array of underlying conditions, such as diabetes, hypertension, chronic obstructive pulmonary disease (COPD), and cancer. It remains poorly understood how these conditions influence the severity of COVID-19. Expansion of the CD28^null senescent T-cell populations, a common phenomenon in aging and several chronic inflammatory conditions, is associated with higher morbidity and mortality rates in COVID-19. Here, we summarize the potential mechanisms whereby CD28^null cells drive adverse outcomes in disease and predispose patients to devastating COVID-19, and discuss possible treatments for individuals with high counts of CD28^null senescent T-cells.

Keywords: CD28null T-cells; COVID-19; cytotoxicity; immune decline; inflammation; senescence.

Figure 1

Molecular characteristics of CD28^null senescent T-cells. Persistent stimuli from various chronic conditions and/or interaction with regulatory T (T_R) cells lead to a senescent phenotype of effector T-cells (see T_R-mediated senescence in “Mechanisms underlying CD28^null cells-associated adverse consequences” below). These senescent T-cells down-regulate costimulatory molecule CD28 and express increased levels of surface molecules, OX40, 4-1BB and NK-like receptors. Because of accumulation of DNA damage and alteration of metabolic and epigenetic programs, these cells largely lose their proliferation ability. These cells are resistant to apoptosis and steroid treatment and gain a senescence-associated secretory phenotype (SASP).

Figure 2

Molecular and cellular basis whereby CD28^null senescent T-cells lead to adverse outcomes. (A) CD28^null senescent T-cells resist to apoptosis and migrate to bone marrow (BM), where they compete in limited lymphoid niches, which leads to decreased output of mature B cells and T-cell progenitors. A decrease in T-cell progenitors further results in thymic dystrophy and impaired T-cell development. Decreases in B and T-cell replenishment lead to narrowed antigenic diversity. (B) CD28^null senescent T-cells interact with dendritic cells (DCs) and tolerize DCs by induction of high levels of inhibitory receptors, ILT3 and ILT4, and repression of CD28/CTLA4 ligands, CD80 and CD86, contributing to immune suppression. (C-D) CD28^null senescent T-cells possess a SASP. (C) After receiving stimuli from alternative costimulatory molecules, OX40 and 4-1BB, and NK-like receptors, CD28^null cells actively express cytotoxic mediators, perforin and granzymes, which mediate unrestricted tissue damage and release of damage-associated molecular patterns (DAMPs). DAMPs enhance immune responses. (D) CD28^null cells also produce pro-inflammatory cytokines, such as IL-6, IL-17, TNFα, and IFNγ, contributing to worsening cytokine release syndrome (“cytokine storm”) in infectious diseases, such as COVID-19.