Marion Humbert (1), Anna Olofsson (1), David Wulliman (2), Julia Niessl (2), Emma Holdcroft (3,4), Fritjof Lund-Johansen (5), Maria C Jenmalm (6), Hans-Gustaf Ljunggren (2), Marcus Buggert (2), Annika C. Karlsson (1)

Affiliates

(1) Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Sweden. (2) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Sweden. (3) Biozentrum, University of Basel, Switzerland. Swiss Institute of Bioinformatics, Switzerland. (4) Institute of Social and Preventive Medicine, University of Bern, Switzerland. 5Department of Immunology, Oslo University, Hospital, Norway. ImmunoLingo Convergence Center, Institute of Clinical medicine, University of Oslo, Norway. (6) Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Sweden.

Abstract

Common cold coronaviruses (CCCs) are believed to induce CD4+ T cells recognizing SARS-CoV-2 peptides in unexposed individuals. However, questions remain regarding the T cells’ specificity, functionality in relation to age and role in disease control. Our study aims to characterize CCC-OC43-specific CD4+ T cell responses in relation to age and to compare humoral and cellular OC43-specific responses to the cross-reactive T cell response of SARS-CoV-2.

Humoral and CD4+ T cell immunity against CCCs and SARS-CoV-2 were evaluated in SARS-CoV-2 seronegative children at age 2 (2yo, n=17) and 6 (6yo, n=16), and adults (n=55). OC43- and SARS-CoV-2 -specific CD4+ T cells were characterized after a 10h stimulation with either OC43- or SARS-CoV-2-derived peptide megapools using activation induced markers and intracellular cytokine staining assays with flow cytometry.

OC43-spike-specific antibodies and CD4+ T cells were prevalent already at 2yo and maintained their levels into adulthood. SARS-CoV-2 cross-reactive CD4+ T cells were detected in all cohorts but were significantly more common in 6yo than adults, with positive responses in 69% and 46% of donors respectively. Furthermore, a close correlation between the OC43-spike-specific and SARS-CoV-2-spike-specific CD4+ T cell responses was present in 6yo (r =0.68, p=0.005) and adults (r=0.64, p<0.0001), but not in 2yo. The functional capacity of OC43-specific CD4+ T cells increased between 2yo and 6yo, reflected by the enhanced production of IFN- and TNF in 6yo. Cross-reactive SARS-CoV-2-specific responses had reduced functional capacity compared to donor-paired OC43-specific responses in all cohorts. Age-dependent phenotypic changes to OC43-specific CD4+ T cells were observed between 2yo, 6yo and adults and included the downregulation of TIGIT and CD38 and the upregulation of CD226 with increasing age. Similar trends were observed in SARS-CoV-2 cross-reactive CD4+ T cell responses.

We show that while OC43-specific CD4+ T cells develop within the first years of life, their function and phenotype are age-dependent. Similarly, modest T cell cross-reactivity to SARS-CoV-2 was observed in all cohorts but peaked at 6yo. The higher prevalence of SARS-CoV-2 cross-reactive CD4+ T cells in 6yo may partly explain why children rarely develop severe COVID-19.