Dynamic changes in innate immune and T cell function and composition at the nasal mucosa across the human lifespan

Abstract

24The very young and very old are at increased risk of serious infections, including 25 pneumonia. This may relate to changes in the immune system as young children have 26 limited immunological memory, while immunosenescence, inflammaging and a decreased 27 pool of naïve immune cells are described with advanced age. How the immune system 28 changes with age at mucosal surfaces, from where infections frequently develop, is not 29 very clear as access to human tissue samples is limited. Therefore, we aimed to assess 30 the composition and activation state of the immune system at the human mucosa. Here, 31 we profiled nasal immune cells from 207 individuals between 1 to 80 years old using flow 32 cytometry. Neutrophil and monocyte functionality were measured using whole blood 33 assays. Levels of thirty nasal cytokines were measured from nasal lining fluid. 34Nasopharyngeal colonization by Streptococcus pneumoniae was assessed using 35 classical microbiology and associated with immune responses. We found that young 36 children have a striking paucity of granulocytes at the nasal mucosa compared to adults. 37In addition, T cell numbers at the nasal mucosa decreased progressively with age and 38 were almost absent in older adults. While nasopharyngeal colonization by Streptococcus 39 pneumoniae was associated with elevated levels of inflammation it had a limited effect on 40 nasal immune composition, including levels of monocytes and neutrophils. These results 41show that the immune system at the nasal mucosal surface changes drastically with age 42 and provides explanations for the increased susceptibility to infections in young and old 43 age. 44Significance statement 45 How the immune system changes with age is an intensive area of research, but has been 46 primarily studied in blood. However, blood poorly reflects the immune system at the 47 mucosa, from where infections develop. This manuscript provides a first characterization 48 of how the composition and function of the immune system in the upper respiratory tract 49 changes with age, providing explanations for increased susceptibility to infection in the 50 very young and old. Furthermore, by linking mucosal and systemic measurements with 51 pneumococcal colonization, we observed that reduced monocyte and neutrophil 52 responses associate with the increased burden of pneumococcal colonization in children. 53This study highlights the need to study the immune system also at other mucosal sites in 54 the context of aging. 55 Abbreviations: 56 Spn; Streptococcus pneumoniae 57 MPO; Myeloperoxidase 58 LPS; Lipopolysaccharide 59 60 61 Results 106 Composition and activation of nasal immune cells changes with age 107Here, we phenotyped nasal cells collected using minimally-invasive nasal microbiopsies 108 (Figure 1). Individuals were grouped as children (1-5 years old, n=43), young adults (18-109 49 years old, n=121) or older adults (50-80 years old, n=43, Table 1). Samples from 110 children were obtained during planned procedures under general anaesthesia such as...

Prolonged activation of nasal immune cell populations and development of tissue-resident SARS-CoV-2 specific CD8 T cell responses following COVID-19

“…CD16 dim neutrophils were even more strongly increased during acute infection (median 256.8x) and ERS (median 11.9x). Such CD16 dim neutrophils might correspond to activated neutrophils as previously they have been shown to correlate with nasal myeloperoxidase levels and/or they might be related to immature banded neutrophils, recently released from the bone marrow 24,25 . Furthermore, CD16 neg granulocytes, which may in part consist of eosinophils, were increased compared to controls 254.1x and 24.3x during acute stage and ERS, respectively.…”

Pneumococcal colonization impairs mucosal immune responses to Live Attenuated Influenza Vaccine in adults

“…It is possible that this short-term window may not reflect accurately the overall effect of a colonization episode on LAIV immune responses. Any LAIV effect in children may be differential due to lower antibody titres to influenza, higher natural rates of pneumococcal colonization and higher levels of inflammation compared to young adults (59). A future paediatric study, whereby colonization status would be assessed before LAIV administration and correlated with immune responses to the vaccine, would provide important insights into the magnitude of pneumococcal effect on vaccine immunogenicity in this population.…”

Experimental Human Challenge Defines Distinct Pneumococcal Kinetic Profiles and Mucosal Responses between Colonized and Non-Colonized Adults

“…One limitation to our study is that it uses an experimental challenge of adults. Therefore, findings might not be generalizable to infants or young children, as important differences in immune system and susceptibility to pneumococcus exist between adults and children ( 32 ). Moreover, it is possible that colonization dynamics during experimental challenge are different from those during natural exposure.…”