Work

The role of age and complement in CD8+ T cell function during human metapneumovirus (HMPV) infection

Year: 2024

Type: article

Abstract: Human metapneumovirus (HMPV) is a leading cause of severe respiratory disease in young children <5yrs old, older adults >65yrs old, and the immunocompromised. HMPV immunity is incomplete with re-infections occurring throughout childhood and adulthood. Re-infections usually result in mild, self-resolving disease except in the elderly, who are at risk for severe disease and co-morbidities. The aged immune response to respiratory viruses such as HMPV is not fully understood. Aging studies have identified marked CD8+ T cell dysfunction due to cell-intrinsic epigenetic changes in gene expression and subsequent function. Thus, we hypothesized that age-related CD8+ T cell dysfunction contributes to severe respiratory disease in the aged host. We found that aged mice produced fewer HMPV tetramer+ CD8+ T cells, which had higher PD-1 expression and other inhibitory receptors and were less polyfunctional with decreased granzyme B. Previous studies have also identified an integral role of PD-1/L signaling in CD8+ T cell function in a young host. Blockade of PD-1/L signaling improves CD8+ T cell antiviral function in young mice. We further hypothesized that PD-1/L signaling was also critical to rejuvenate exhausted CD8+ T cells in the aged host. We found that removal of PD-1 improved granzyme B production and reduced the accumulation of cytotoxic tissue-resident memory CD8+ T cells in the aged host. In a concurrent study, we investigated other regulators of CD8+ T cell function during HMPV infection. Notably, we found that the complement protein, C1q, produced by inflammatory monocytes modulates CD8+ T cell antiviral function through the receptor, gC1qR. Taken together, this work explores the relationship between severe respiratory disease in an aged mouse model and CD8+ T cell function upon primary infection and re-challenge, the role of PD-1/L signaling in aged CD8+ T cell antiviral function, and identifies C1q as a novel regulator of CD8+ T cell function.

Source: D-Scholarship@Pitt (University of Pittsburgh)

Author: Parks, Olivia B

Language: English

Topic: Respiratory viral infections research

Subfield: Epidemiology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: green

Funders: University of Pittsburgh, Hillman Foundation, National Institutes of Health, National Institute of Allergy and Infectious Diseases

Awards: G2354209684, G9000009745, G9000133895, Host Determinants of Human Metapneumovirus Immunity and Pathogenesis

OpenAlex ID: W7052368341