Function, homing, and residency of T-cell immune responses against SARS-CoV-2

ABSTRACT

Background: In order to inform vaccine development on the correlates of protection against SARS-CoV-2, we performed detailed phenotypic and functional analyses in clinically-defined groups of patients recruited during the first wave of SARS-CoV-2 infection, including the assessment of Resident Memory T cells (TRM) in lung of convalescent patients. Methods: Blood samples from 46 participants diagnosed with acute COVID-19 (14 symptomatic non-hospitalized;20 mild-hospitalized and 12 severehospitalized) were obtained 7-16 days after symptoms onset. Lung biopsies were obtained from three convalescent patients 1 to 7.5 months after initial infection. The phenotype and functional capabilities of SARS-CoV-2-specific CD4+ and CD8+T cells were measured by FACS after stimulation with a pool of overlapping SARS-CoV-2 viral peptides (M, N and S). Results: Pattern variations associated with viral-specific T cell responses where based on two factors, the targeted viral protein and the cohort of patients assessed. Overall, stimulation with M and N viral peptides induced a Th1 profile exemplified by IFNg production in CD4+T cells and degranulation in CD8+T cells respectively, whereas S peptides induced a Th2 profile exemplified by IL-4. Hospitalized patients showed increased IFNg secretion in CD4+T cells in response to any viral protein compared to non-hospitalized patients (p=0.020 for M and S peptides in the mild group;p=0.004 for M, p=0.011 for N and p=0.007 for S peptides in the severe group;Figure 1) and IL-4 secretion in CD8+T cells in response to S peptides (p=0.004 and p=0.003 for mild and severe patients, respectively). In contrast, the expression of IL-10, which was mostly expressed in CCR7+ cells, was significantly increased in CD4+T cells from non-hospitalized patients after stimulation with M peptides when compared to the mild COVID-19 group (p=0.035). Importantly, SARS-CoV-2 specific T cell responses with a biased TRM profile were detected up to 7.5 months after infection in the lung of convalescent patients. However, tissue responses strongly differed from blood. Conclusion: Our results suggest that a balanced anti-inflammatory antiviral response promoted by non-spike proteins may be key to favor infection resolution without major complications. Further, while immune responses migrate and establish in the lung as resident memory T cells, the magnitude and profile of the lung SARS-Cov-2 specific T cells strongly differ from the response detected in blood.