Developmental Regulation of Effector and Resident Memory T Cell Generation during Pediatric Viral Respiratory Tract Infection

Abstract

Viral respiratory tract infections (VRTI) remain a leading cause of morbidity and mortality among infants and young children. In mice, optimal protection to VRTI is mediated by recruitment of effector T cells to the lungs and respiratory tract, and subsequent establishment of tissue resident memory T cells (Trm), which provide long-term protection. These critical processes of T cell recruitment to the respiratory tract, their role in disease pathogenesis, and establishment of local protective immunity remain undefined in pediatric VRTI. In this study, we investigated T cell responses in the upper respiratory tract (URT) and lower respiratory tract (LRT) of infants and young children with VRTI, revealing developmental regulation of T cell differentiation and Trm generation in situ. We show a direct concurrence between T cell responses in the URT and LRT, including a preponderance of effector CD8 T cells that was associated with disease severity. During infant VRTI, there was an accumulation of terminally differentiated effector cells (effector memory RA T cells) in the URT and LRT with reduced Trm in the early neonatal period, and decreased effector memory RA T cell and increased Trm formation with age during the early years of childhood. Moreover, human infant T cells exhibit increased expression of the transcription factor T-bet compared with adult T cells, suggesting a mechanism for preferential generation of effector over Trm. The developmental regulation of respiratory T cell responses as revealed in the present study is important for diagnosing, monitoring, and treating VRTI in the critical early life stages.

The Whole Body as the System in Systems Immunology

“…The majority of these tissue memory cells comprise noncirculating T RM cells that exhibit distinct phenotypic and transcriptional profiles that enable their retention in tissue sites ( Hombrink et al., 2016 ; Kumar et al., 2017 ); tissue-specific proportions of T RM in each site are stably maintained with age ( Senda et al., 2019 ; Thome et al., 2014 ). Given that T RM are formed early in life and can be detected in mucosal sites in infants and children and during an active infection ( Connors et al., 2018 ; Thome et al., 2016a ), it is possible that T RM maintain long-term immunity for maintenance of tissue homeostasis.…”

Dissecting the defects in the neonatal CD8+ T-cell response

“…Samples collected from the upper respiratory tract and lower respiratory tract from human infants infected with a respiratory virus demonstrate a propensity toward expansion of terminally differentiated effector cells and reduced mature tissue resident memory (TRM) formation based on CD103 expression . This increased effector T‐cell infiltration is associated with lung injury . Two‐week old mice infected with influenza virus demonstrate comparable numbers of viral‐specific CD8 + T cells in the lungs at day 12–15 postinfection adult mice .…”

“…119 This increased effector T-cell infiltration is associated with lung injury. 119 Two-week old mice infected with influenza virus demonstrate comparable numbers of viral-specific CD8 + T cells in the lungs at day 12-15 postinfection adult mice. 120 Despite the prevalence of the viralspecific CD8 + T cells during acute infection, mice infected at 2 weeks of age have reduced TRM in adulthood, and, more importantly, this reduced TRM population provides less protection compared to adults rechallenged with a heterosubtypic virus mice.…”

“…120 In addition, more immature mice at 3 days of age have greatly diminished CTL responses to both dominant and subdominant epitopes for influenza virus. In contrast, 7-day old mice have normal CTL responses to the dominant PA (224)(225)(226)(227)(228)(229)(230)(231)(232)(233) and subdominant NS2 (114)(115)(116)(117)(118)(119)(120)(121) epitopes. These 7-day old mice mounted a NP (366)(367)(368)(369)(370)(371)(372)(373)(374) response that was intermediate between that of 3-day old and adult mice.…”

In-silico immune cell deconvolution of the airway proteomes of infants with pneumonia reveals a link between reduced airway eosinophils and an increased risk of mortality

“…Sampling of the airway by these methods typically results in limited cell yields and the cells that are recovered are generally highly enriched for granulocytes, complicating detailed characterisation of less abundant phenotypes using traditional flow cytometry-based tools 8 . Recent analysis of the cellular composition of upper airway by flow cytometry showed that the typical abundances of critical effector cells like T Cells, B Cells, Mast cells, Dendritic cells and NK cells to be less than 0.5% of all airway cells, while granulocytes were present at a median frequency of >90% 9 .…”