Antiviral T cell immunity in relation to age and infection history

Children and elders have an increased risk of severe disease to many infections that pose little risk in healthy young adults. In children this is attributed to their lack of immunological memory, and in elders it is believed to be a combination of increased frailty and declining immune function. Besides age, the memory (m) T cell repertoire is further shaped by the pathogens encountered throughout life. Yet, the quality of antigen-specific T cell responses against the most common viral infections are rarely studied in relation to age and previous infections. Thus, the overarching aim of this thesis was to explore the interaction of age and infection history on the phenotype and function of antigen-specific mT cells against common acute and chronic viruses using high-parameter flow cytometry and single-cell RNA sequencing.

During the 2019 pandemic, the low incidence of severe COVID-19 in children was hypothesized to be due to cross-reactivity between endemic human coronaviruses (HCoV) and SARS-CoV-2. Our findings in Paper I supported this hypothesis, showing that cross-reactivity exist between HCoV-OC43 and SARS- CoV-2, and that both the prevalence and function of cross-reactive mCD4+ T cells against SARS-CoV-2 peak in childhood and decline with age.

Infection by human immunodeficiency virus (HIV) requires life-long treatment, and still promotes immune-altering mechanisms on the immune system. In Paper II, we investigated the function of antiviral T cell immunity to common viruses in children living with HIV (CLWH). Compared to HIV-negative children, CLWH displayed a more adult-like mT cell compartment, such as elevated cell senescence. Particularly mT cells targeting the chronic viruses Epstein Barr virus (EBV) and Cytomegalovirus (CMV) were affected, with CMV-specific mCD8+ T cells displaying extensive clonal expansion in CLWH.

Because young adults rarely develop severe disease from endemic respiratory viruses, including SARS-CoV-2, Paper III aimed to deepen our understanding of the qualities associated with an effective antiviral T cell response in this group. We found that antigen-specific mCD4+ T cells against the included viruses were prevalent and highly specialized by antigen-specificity, and that SARS-CoV-2- specific mCD4+ T cells mature alongside IgG seroconversion.

That the function of the immune system declines with advancing age is well known, but in paper IV, we asked whether this decline would be further exacerbated at the end of life. By comparing mT cell and antigen-specific mT cell responses in elderly end-of-life patients in palliative care to healthy elders, we found that cell-mediated immunity remained functional until the end, contrasting our initial hypothesis. Notably, the frequency of cytotoxic mCD4+ T cells increased the last 30 days of life.

In conclusion, the constituent work in this thesis underscores the adaptability and resilience within cell-mediated immunity that carries us through life. These findings may aid in the evaluation of new vaccines, antivirals and other clinical interventions with implications for cell-mediated immunity.

List of scientific papers

I. Humbert M*, Olofsson A*, Wullimann D, Niessl J, Hodcroft EB, Cai C, Gao Y, Sohlberg E, Dyrdak R, Mikaeloff F, Neogi U, Albert J, Malmberg KJ, Lund-Johansen F, Aleman S, Björkhem-Bergman L, Jenmalm MC, Ljunggren HG, Buggert M, Karlsson AC. Functional SARS-CoV-2 cross-reactive CD4+ T cells established in early childhood decline with age. Proc Natl Acad Sci U S A, March 2023;120(12), e2220320120 https://doi.org/10.1073/pnas.2220320120

II. Olofsson A, Humbert M, Cai C, Scharf L, Tauriainen J, Soeria Atmadja S, Hagey D, Thalme A, Buggert, M, Navér L, Karlsson AC. Altered antiviral T cell immunity against common viruses in pediatric HIV [Manuscript]

III. Olofsson A*, Lee JQ*, Björkander S, Buggert M, Melen E, Karlsson AC Distinct antiviral T cell immunity patterns against common viruses and its correlation with SARS-CoV-2 seroconversion [Manuscript]

IV. Olofsson A, Humbert M, Rekha RS, Frankling MH, Lund-Johansen F, Bergman P, Björkhem-Bergman L, Karlsson AC Adaptive immune responses against common viruses are sustained and functional in end-of-life patients iScience, March 2025;28(3):112082 https://doi.org/10.1016/j.isci.2025.112082

*These authors contributed equally to this work