High-dimensional immune profiling identifies circulating NK and T cell subpopulations associated with asymptomatic COVID-19 and absence of multiple long-term symptoms

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COVID-19 includes a wide spectrum of clinical presentations ranging from asymptomatic to severe disease and death. While immune mechanisms associated with severe disease in hospitalized patients have been intensively investigated, less is known about immune signatures protecting against symptomatic disease and long-term symptoms in unvaccinated, non-hospitalized individuals. We applied high-dimensional single-cell immune profiling of peripheral blood mononuclear cells, T cell activation-induced marker assay and serological assays to identify immune cell populations, cross-reactive pre-immunity and protein biomarkers associated with asymptomatic or moderate disease as well as long-term symptoms in a longitudinal SARS-CoV-2 household study at acute infection and after six months. Asymptomatic infection was associated with higher frequencies of CD57 + TIGIT + NKT and granzyme B-secreting NKT cells as well as higher frequencies of CD16 + TIGIT + NK and CD4 + CD57 + GrB + effector T cells, that also were detected after six months. Lower serum IL-1RA and hepatic growth factor (HGF) levels were also associated with asymptomatic infection. Upon PMA + ionomycin stimulation, higher frequencies of polyfunctional CD4 + and CD8 + effector T cells were observed in asymptomatic compared to moderately ill cases. Absence of multiple long-term symptoms was associated with higher frequencies of CD16 + TIGIT + NK cells, lower HGF serum levels and higher polyfunctional CD8 + T cell levels upon stimulation, thereby sharing characteristics with asymptomatic infection. Pre-existing T cell responses against hCoV and SARS-CoV-2 peptides were higher in non-infected compared to infected participants. The results contribute to increased understanding of immune cells potentially protecting against acute and multiple long-term symptoms in non-hospitalized SARS-CoV-2 infected individuals involving defined subpopulations of NK and T cells. • Longitudinal immune profiling of asymptomatic and moderate COVID-19 and cases with and without long-term symptoms. • Higher frequencies of NK, NKT and CD4 T cell subpopulations and lower serum HGF and IL-1RA levels in asymptomatic compared to moderate cases. • Low HGF level and persisting high frequencies of subpopulations of memory B and regulatory NK cells in cases without long-term symptoms. • Higher levels of CD16 + TIGIT + NK cells in non-infected, asymptomatic, and cases without long-term symptoms compared to moderate disease. • Higher cross-reactive T cell responses in asymptomatic and non-infected compared to moderate cases.