Abstract
A substantial proportion of patients who have recovered from coronavirus disease-2019 (COVID-19) experience COVID-19–related symptoms even months after hospital discharge. We extensively immunologically characterized patients who recovered from COVID-19. In these patients, T cells were exhausted, with increased PD-1+ T cells, as compared with healthy controls. Plasma levels of IL-1β, IL-1RA, and IL-8, among others, were also increased in patients who recovered from COVID-19. This altered immunophenotype was mirrored by a reduced ex vivo T cell response to both nonspecific and specific stimulation, revealing a dysfunctional status of T cells, including a poor response to SARS-CoV-2 antigens. Altered levels of plasma soluble PD-L1, as well as of PD1 promoter methylation and PD1-targeting miR–15-5p, in CD8+ T cells were also observed, suggesting abnormal function of the PD-1/PD-L1 immune checkpoint axis. Notably, ex vivo blockade of PD-1 nearly normalized the aforementioned immunophenotype and restored T cell function, reverting the observed post–COVID-19 immune abnormalities; indeed, we also noted an increased T cell–mediated response to SARS-CoV-2 peptides. Finally, in a neutralization assay, PD-1 blockade did not alter the ability of T cells to neutralize SARS-CoV-2 spike pseudotyped lentivirus infection. Immune checkpoint blockade ameliorates post–COVID-19 immune abnormalities and stimulates an anti–SARS-CoV-2 immune response.
Highlights
A large proportion of patients discharged after being hospitalized for COVID-19 experience the persistence of COVID-19–related symptoms [1,2,3,4,5], a condition defined as “long COVID” [6]
While the proportion of CD40L-expressing CD4+ T cells and that of ICOS-expressing CD8+ T cells was decreased in patients who recovered from COVID-19 as compared with patients with COVID-19 (Table 2), the fraction of OX40+ and GITR+ CD8+ T cells of patients who recovered from COVID-19 exceeded that of healthy controls, with the latter marker being the highest observed among all groups (Table 2)
In the evaluation of exhaustion markers, CD127+ and PD-1+ CD4+ T cell subpopulations were increased in patients who recovered from COVID-19 as compared with healthy controls, and they were at comparable levels to those observed in patients with COVID-19 (Figure 1, A–D), while 2B4+CD4+ T cell levels were similar to that of healthy controls but higher compared with patients with COVID-19 (Figure 1, E and F)
Summary
A large proportion of patients discharged after being hospitalized for COVID-19 experience the persistence of COVID-19–related symptoms [1,2,3,4,5], a condition defined as “long COVID” [6]. During the acute phase of COVID-19, a variety of immune alterations are evident, including lymphopenia and proinflammatory cytokine storm [7,8,9,10,11,12,13,14] These immune disorders denote a broad functional impairment occurring in both the innate and adaptive compartments of the immune system that may affect the ability to counteract SARS-CoV-2 infection. Increasing evidence suggests that phenotypic and functional alterations of the immune system persist long after recovery from COVID-19 [15,16,17] These immune abnormalities may dampen an efficient immune response against viral reinfections and may overall impair a person’s ability to fight pathogens [18,19,20]. A method to elicit a successful reversal of post–COVID-19 immune abnormalities may be necessary as long-term COVID-19 symptoms cause, in some cases, serious afflictions, and this strategy could be significantly clinically relevant
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