The role of tissue resident memory T cells in the respiratory mucosal immune response in humans

Abstract

Tissue resident memory T (TRM) cells represent a population of effector memory T cells that persist in peripheral tissues and act as sentinels of the adaptive immune response, facilitating rapid and specific immune responses to pathogens at the site of entry or infection. The central hypothesis of this thesis is that TRM cells play a crucial role in providing persistent mucosal protective immunity against respiratory microbes. This study aimed to develop methods to identify and quantify antigen-specific TRM cells in human respiratory tissue and apply these techniques to evaluate mucosal immune responses post infection or vaccination and during bacterial colonisation.

Assays to identify antigen specific T cells and TRM cells in human tonsil tissue and broncho alveolar lavage fluid (BALF) were developed and optomised. A novel nasal sampling technique was developed to facilitate repeated, non-invasive sampling of nasal mucosal immune cells to enable assessment of mucosal TRM responses in healthy donors. Several cohorts of patients and healthy donors were established to evaluate T cell responses in the respiratory tract.

Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection induces antigen-specific CD4+ and CD8+ T cell responses in blood, however there is limited data on the on T cell responses in the respiratory tissue following infection or immunisation with SARS-CoV-2 vaccines. This study demonstrated that the frequency of SARS-CoV-2 spike (S)-specific IFN-y+ CD4+ and CD8+ T cells was enhanced in the blood post immunisation with SARS-CoV-2 mRNA vaccines. In contrast, S-specific IFN-y-producing CD4+ or CD8+ TRM were not induced in the nasal mucosa by parenteral immunisation with SARS-CoV-2 mRNA vaccines.

Bordetella pertussis is the third leading cause of vaccine-preventable deaths in under-5s, despite high global vaccination coverage. This may reflect rapidly waning immunity following immunisation with acellular pertussis (aP) vaccines, which replaced whole cell pertussis (wP) vaccines in the 1990-2000s. Adults immunised with wP vaccines as infants had significantly more B. pertussis-specific IL-17+ CD4+ TRM in nasal mucosa and IFN-y+ CD4+ TRM in tonsil than adults immunised with aP vaccine as infants.

The immune imprint of nasal colonisation with Staphylococcus aureus and how colonisation may influence the immune response following invasive disease or vaccination is poorly understood. S. aureus-specific IFN-y+ CD4+ T cell responses in tonsil were significantly suppressed in individuals colonised with S. aureus. Furthermore, S. aureus-specific IL-17+ CD4+ T cells and the frequencies of TRM cells in the nasal mucosa were significantly lower in individuals nasally colonised with S. aureus compared with non-colonised controls. The expression of IL-10 in nasal mucosa was higher in persistent S. aureus carriers.

This study has developed and implemented a novel non-invasive nasal mucosal sampling method to study antigen-specific T cell responses in the upper respiratory tract. The work has provided new and clinically important insights into host pathogen interactions in the respiratory mucosa in humans for three pathogens of global importance, SARS-CoV-2, B. pertussis and S. aureus. The findings will be of significant benefit to the field in advancing of our understanding of respiratory mucosal cellular immune responses and their role in protection against infection of the respiratory tract.