TINO: T Cells in the Nose of Older Adults

Study Overview
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Brief Summary
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Rationale: Individuals with advanced age are at a progressively increasing risk of acquiring lower respiratory tract infections. Besides calendar age, the degree of frailty also associates with increased susceptibility to pneumonia requiring hospitalization. How alterations in the mucosal immune system with advanced age predispose to infections remains unclear as access to relevant tissue samples is limited. With minimally-invasive nasal sampling methods, it was recently observed that in vital older adults, both CD4+ T cells and CD8+ T cells are selectively lost from the nasal mucosa. However, the exact phenotype, underlying mechanisms, key molecules and consequences of this have not yet been investigated. Objective: Elucidate the mechanisms underlying the loss of nasal T cells and characterize in depth the differences of T cells in young and older adults and associate this loss with susceptibility to infections. Study design: Prospective cohort study Study population: Participants will be recruited from 3 groups: healthy young adults (18-30 years, n=50) vital older adults (>65 years, n=60) frail elderly (>65 years, n=60). This group includes individuals without a history of recurrent respiratory infections or with >2 self-reported episodes of respiratory infection in the past year. Main study parameters/endpoints: Frequency of nasal CD8+ T cells in young adults and frail older adults. Secondary study parameters/endpoints: Phenotype (subsets, activation status), functionality, transcriptomic state, clonality and frequency of nasal and blood T cell populations Stability of T cells and other immune parameters, as described for main study parameter, during a second sample after 3 months. Analysis of other immune populations as for main study parameter Concentration of nasal and systemic factors (e.g. cytokines and metabolites) and their association with T cells and other immune populations Respiratory tract microbiota profiles and presence of asymptomatic viral infections and their association with T cells and other immune parameters Chronological and biological age, sex, and other immunologically relevant parameters with T cell populations and other immune parameters Alteration of T cell phenotype, during and following respiratory tract infections. Levels of antigen-specific T cells and other immune parameters in nose and blood post infection.

Official Title
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TINO: Identifying the Underlying Mechanisms and Consequences of the Loss of Nasal T Cells in Vital and Frail Older Individuals

Conditions
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Aging, Respiratory Tract Infections

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: •Adults able and willing to provide informed consent. Specific inclusion criteria per group: Young adults aged 18-30 years old Healthy elderly aged >65 years old Frail elderly >65 years old Clinical Frailty score healthy elderly 1-3 Clinical Frailty score frail elderly >3 Self-reported respiratory tract infection in previous year healthy elderly 0-1 Self-reported respiratory tract infection in previous year frail elderly 0-1 or >1 Exclusion Criteria: Incompetence to provide informed consent prior or during study Current smoker or >40 pack year history History of severe nose bleedings Diagnosed with asthma, COPD or chronic rhinosinusitis Use of inhalation corticosteroids or antibiotics in the past 6 weeks Current use of anti-coagulants (to prevent nosebleeds). Platelet inhibitors like acetylsalicylzuur (Ascal) are allowed. Respiratory tract infection or common cold in the past 2 weeks Immunocompromised individuals (with primary immune deficiency or secondary immune deficiency) Life expectancy <28 days in the opinion of study physician Vaccination in the 2 months prior to study start. A potential subject that is only excluded from participation based on a recent vaccination will be asked to re-participate 2 months post vaccination.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Young adults<br>N=50 of this group No intervention. Sampling at timepoint 0 and for 50% of the group another sample at 3 months If respiratory symptoms develop in the 3 months after timepoint 0, participants are invited to provide a NPS/OPS to identify causative agent, and if one is established, individuals are sampled 3 more times at months 1, 3 and 5 post symptom onset | |
| Vital elderly<br>N=60 of this group No intervention. Sampling at timepoint 0 and for 50% of the group another sample at 3 months If respiratory symptoms develop in the 3 months after timepoint 0, participants are invited to provide a NPS/OPS to identify causative agent, and if one is established, individuals are sampled 3 more times at months 1, 3 and 5 post symptom onset | |
| Frail elderly<br>N=60 of this group. Half with recurring respiratory infections, and half without No intervention. Sampling at timepoint 0 and for 50% of the group another sample at 3 months If respiratory symptoms develop in the 3 months after timepoint 0, participants are invited to provide a NPS/OPS to identify causative agent, and if one is established, individuals are sampled 3 more times at months 1, 3 and 5 post symptom onset | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of nasal CD8+ T cells in young adults and frail older adults. | CD8 T cells relative to nasal epithelial cells (ratio) | baseline sample or month 3 sample | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phenotype of nasal and blood T cell populations in young adults, healthy older adults and frail older adults that suffer from recurrent respiratory tract infections or not. | percentage of T cells and T cell subsets | baseline sample or month 3 sample | 
| Functionality of nasal and blood T cell populations in young adults, healthy older adults and frail older adults that suffer from recurrent respiratory tract infections or not. | percentage of T cells responding to in vitro stimulations | baseline sample or month 3 sample | 
| Transcriptomic cluster composition of nasal and blood T cell populations in young adults, healthy older adults and frail older adults that suffer from recurrent respiratory tract infections or not, as frequency of T cell subsets. | T cell clusters based on gene expression patterns | baseline sample or month 3 sample | 
| Clonality of nasal and blood T cell populations in young adults, healthy older adults and frail older adults that suffer from recurrent respiratory tract infections or not. | Number and proportion of TCR clones | baseline sample or month 3 sample | 
| Stability of nasal T cells, as described for main study parameter, during a second sample after 3 months. | CD8 T cells relative to nasal epithelial cells (ratio) | baseline sample versus month 3 sample | 
| Stability of nasal immune populations, during a second sample after 3 months. | immune cell populations relative to nasal epithelial cells (ratio) | baseline sample versus month 3 sample | 
| Comparison of nasal immune cell populations between young adults, vital and frail elderly | ratio to epithelial cells | baseline sample or month 3 sample | 
| Comparison of peripheral immune cell populations between young adults, vital and frail elderly | percentage of total CD45+ cells | baseline sample or month 3 sample | 
| Concentration of nasal and systemic cytokines | concentrations | baseline sample or month 3 sample | 
| Concentration of nasal and systemic metabolitesother immune populations | concentrations | baseline sample or month 3 sample | 
| Respiratory tract microbiota profiles and their association with T cells and other immune parameters | microbiota abundance (total sum scaling) | baseline sample or month 3 sample | 
| Presence of asymptomatic viral infections and their association with T cells and other immune parameters | viral of loads (Ct) | baseline sample or month 3 sample | 
| Effect of sex on aging effects of nasal immune populations | ratio to nasal epithelial cells | baseline sample or month 3 sample | 
| Effect of sex on aging effects of blood immune populations | percentage of CD45+ cells | baseline sample or month 3 sample | 
| Frequencies of antigen-specific T cells in nose post infection. | antigen-specific T cells as percentage of T cells | symptom onset and 1, 3 and 5 months later | 
| Frequencies of antigen-specific T cells in blood post infection. | antigen-specific T cells as percentage of T cells | symptom onset and 1, 3 and 5 months later |