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

Publication date: Jul 11, 2025

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 CD57TIGITNKT and granzyme B-secreting NKT cells as well as higher frequencies of CD16TIGITNK and CD4CD57GrB 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 CD16TIGITNK 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.

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