Changes in nasal mucosal T cells associated with susceptibility to respiratory infections during aging

B.1.2 Abstract The risk of pneumonia increases with age, and the incidence of pneumonia is expected to double in the coming two decades as the population ages.

The COVID-19 pandemic highlights the urgent need to obtain mechanistic understanding of how the mucosal immune system changes with age and its consequences for the susceptibility of the elderly to respiratory infections. Bridging this knowledge gap will also facilitate the development of mucosal vaccines for this age group.

Substantial efforts have been made to characterize the effects of aging on the systemic immune system, leading for example to the appreciation of the consequences of decreased naïve T cell populations and the process of ‘inflammaging’.

In contrast, the effect of aging on the mucosal immune system remains understudied, even though this is crucial in protecting against infections.

We have recently demonstrated using minimally-invasive nasal sampling methods that T cells are selectively lost from the human nasal mucosa with age.

Importantly, murine models have demonstrated that nasal mucosa tissue-resident memory T cells are crucial for the protection against influenza lung infection. Here, we will elucidate the mechanisms and consequences of this loss of T cells from the mucosa in elderly humans.

Firstly, we will characterize in-depth the exact phenotype of T cell populations in the nose of young and older adults using established protocols for minimally-invasive sampling and mass cytometry and single-cell RNA-Seq analysis.

We will also characterize T cells in paired PBMC samples and perform functional assays using nasal lining fluid on T cell survival and recruitment to delineate exact phenotype in which T cells are lost and provide insights into the underlying causes.

Over a 3-year period, we will include at least 50 young adults, 50 healthy elderly and 50 frail elderly that suffer from recurrent respiratory infections.

We will also collect a second sample per person after a 3-month timeframe to understand the dynamics of the local immune system (n=300 total samples).

In addition, we will include elderly patients with acute respiratory tract infections, who will be followed-up during convalescence.

We will compare patients and age-matched controls (healthy and frail elderly) to associate the presence of specific mucosal T cell populations and activation status with infection and respiratory health.

Paired single-cell RNA-Seq and TCR-Seq during infection and convalescence will be used to assess the induction of local memory.

By coupling innovative mucosal sampling with established state-of-the-art laboratory techniques, this project will provide unique insights into the increased susceptibility to respiratory infections with age.

Successful delivery of this project could therefore identify correlates of protection against infection, and accelerate the development and testing of mucosal vaccines for the elderly.