Generation of Cytotoxic T Cells and Dysfunctional CD8 T Cells in Severe COVID-19 Patients

Abstract

COVID-19, the infectious disease caused by SARS-CoV-2, has spread on a pandemic scale. The viral infection can evolve asymptomatically or can generate severe symptoms, influenced by the presence of comorbidities. Lymphopenia based on the severity of symptoms in patients affected with COVID-19 is frequent. However, the profiles of CD4+ and CD8+ T cells regarding cytotoxicity and antiviral factor expression have not yet been completely elucidated in acute SARS-CoV-2 infections. The purpose of this study was to evaluate the phenotypic and functional profile of T lymphocytes in patients with moderate and severe/critical COVID-19. During the pandemic period, we analyzed a cohort of 62 confirmed patients with SARS-CoV-2 (22 moderate cases and 40 severe/critical cases). Notwithstanding lymphopenia, we observed an increase in the expression of CD28, a co-stimulator molecule, and activation markers (CD38 and HLA-DR) in T lymphocytes as well as an increase in the frequency of CD4+ T cells, CD8+ T cells, and NK cells that express the immunological checkpoint protein PD-1 in patients with a severe/critical condition compared to healthy controls. Regarding the cytotoxic profile of peripheral blood mononuclear cells, an increase in the response of CD4+ T cells was already observed at the baseline level and scarcely changed upon PMA and Ionomycin stimulation. Meanwhile, CD8+ T lymphocytes decreased the cytotoxic response, evidencing a profile of exhaustion in patients with severe COVID-19. As observed by t-SNE, there were CD4+ T-cytotoxic and CD8+ T with low granzyme production, evidencing their dysfunction in severe/critical conditions. In addition, purified CD8+ T lymphocytes from patients with severe COVID-19 showed increased constitutive expression of differentially expressed genes associated with the caspase pathway, inflammasome, and antiviral factors, and, curiously, had reduced expression of TNF-α. The cytotoxic profile of CD4+ T cells may compensate for the dysfunction/exhaustion of TCD8+ in acute SARS-CoV-2 infection. These findings may provide an understanding of the interplay of cytotoxicity between CD4+ T cells and CD8+ T cells in the severity of acute COVID-19 infection.

Alterations in the CD56− and CD56+ T Cell Subsets during COVID-19

“…It has been demonstrated earlier that patients with COVID-19 shifted towards a cytotoxic phenotype in the T cell compartment, as indicated by high degranulation capacity (granzyme B and perforin levels) compared to healthy controls [2]. However, another study found an abnormal CD8 + T cells response characterized by reduced perforin levels in patients with severe COVID-19 [1]. In our study, intracellular levels of granzyme B in CD56 + T cells were higher in the ICU patients compared to HD, while CD56 − T cells in the CCP group had reduced granzyme B + cell content compared to the MS group (Figure 3a).…”

“…Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) leads to complex immune dysregulation and affects different components of the antiviral cellular immunity. In particular, T cell immune response, which plays an essential role in infection control, may vary in patients with mild, moderate, and severe COVID-19 [1,2]. The question about the predictive significance of different T cell markers of activation, differentiation, or exhaustion in COVID-19 remains relevant.…”

The unreversible reduced but persistent activated NK and CD8 + T cells in severe/critical COVID-19 during omicron pandemic in China

“…As of writing this report, we had enrolled 66 COVID-19 admission patients including 17 in the M/M group, 24 in the S group, and 25 in the C group. The median disease duration before admission was 11 days [ 10 , 13 ] in the M/M group, 10 days [ 7 , 14 ] in the S group and 9 days [ 7 , 10 ] in the C group. The median age of patients in the three COVID-19 groups was 70 years [57, 83], 77 years [68, 82], and 74 years [67, 80], respectively.…”

“…In this cohort, the peripheral neutrophilia along with lymphopenia was more pronounced in patients with an S/C condition, which had been indicated as a predictor of the severity of COVID-19 due to the infiltration of neutrophils in the histopathological lung lesion [ 15 ]. Based on our observation, we captured the rapid restoration of peripheral lymphocyte counts in the M/M group rather than the S/C group ( Figure 3 ), as previous data indicated a slow restoration capacity of lymphocytes in most severe cases [ 13 ]. Although the detailed mechanism of the rapid reduction and slow restoration of lymphocyte counts is still unclear, it reminded clinicians to alert to S/C COVID-19 with potentially worse outcomes, as did in SARS [ 11 ].…”

The immune paradox of SARS‐CoV‐2: Lymphocytopenia and autoimmunity evoking features in COVID‐19 and possible treatment modalities

“…SARS‐CoV‐2 spike glycoprotein was capable of inducing a rapid membrane fusion to produce syncytium, which was seen to readily internalise multiple lines of lymphocytes to form typical cell‐in‐cell structures, remarkably leading to the death of internalized cells 21 . Interestingly, prolonged hospitalizations with COVID resulted in no overt recovery of B or CD4+ T cell lymphocytes 22 . Whereas in SARS‐CoV1, CD8+ T lymphocytes normalised after 3 months of symptom onset, and CD4+ lymphocytes were still decreased in almost half of people after a year; total lymphocytes were still decreased after 16 weeks.…”