Tissue-resident memory T cells (TRMs) in mice mediate optimal protective immunity to infection and vaccination, while in humans, the existence and properties of TRMs remain unclear. Here, we use a ...unique human tissue resource to determine whether human tissue memory T cells constitute a distinct subset in diverse mucosal and lymphoid tissues. We identify a core transcriptional profile within the CD69+ subset of memory CD4+ and CD8+ T cells in lung and spleen that is distinct from that of CD69− TEM cells in tissues and circulation and defines human TRMs based on homology to the transcriptional profile of mouse CD8+ TRMs. Human TRMs in diverse sites exhibit increased expression of adhesion and inhibitory molecules, produce both pro-inflammatory and regulatory cytokines, and have reduced turnover compared with circulating TEM, suggesting unique adaptations for in situ immunity. Together, our results provide a unifying signature for human TRM and a blueprint for designing tissue-targeted immunotherapies.
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•CD69+ memory T cells predominate in multiple tissues throughout the human body•A core signature defining human TRMs is enriched within CD69+ tissue memory T cells•Human TRMs have unique adhesion and migratory abilities and functional capacities•Human TRMs exhibiting the core profile populate multiple lymphoid and mucosal sites
Kumar et al. identify a core transcriptional and phenotypic signature that defines human TRMs for both CD4+ and CD8+ T cells that is preserved across diverse individuals and in mucosal and lymphoid sites.
Infants suffer disproportionately from respiratory infections and generate reduced vaccine responses compared with adults, although the underlying mechanisms remain unclear. In adult mice, ...lung-localized, tissue-resident memory T cells (TRMs) mediate optimal protection to respiratory pathogens, and we hypothesized that reduced protection in infancy could be due to impaired establishment of lung TRM. Using an infant mouse model, we demonstrate generation of lung-homing, virus-specific T effectors after influenza infection or live-attenuated vaccination, similar to adults. However, infection during infancy generated markedly fewer lung TRMs, and heterosubtypic protection was reduced compared with adults. Impaired TRM establishment was infant-T cell intrinsic, and infant effectors displayed distinct transcriptional profiles enriched for T-bet-regulated genes. Notably, mouse and human infant T cells exhibited increased T-bet expression after activation, and reduction of T-bet levels in infant mice enhanced lung TRM establishment. Our findings reveal that infant T cells are intrinsically programmed for short-term responses, and targeting key regulators could promote long-term, tissue-targeted protection at this critical life stage.
Infants and young children are more susceptible to common respiratory pathogens than adults but can fare better against novel pathogens like severe acute respiratory syndrome coronavirus 2. The ...mechanisms by which infants and young children mount effective immune responses to respiratory pathogens are unknown. Through investigation of lungs and lung-associated lymph nodes from infant and pediatric organ donors aged 0-13 years, we show that bronchus-associated lymphoid tissue (BALT), containing B cell follicles, CD4
T cells and functionally active germinal centers, develop during infancy. BALT structures are prevalent around lung airways during the first 3 years of life, and their numbers decline through childhood coincident with the accumulation of memory T cells. Single-cell profiling and repertoire analysis reveals that early life lung B cells undergo differentiation, somatic hypermutation and immunoglobulin class switching and exhibit a more activated profile than lymph node B cells. Moreover, B cells in the lung and lung-associated lymph nodes generate biased antibody responses to multiple respiratory pathogens compared to circulating antibodies, which are mostly specific for vaccine antigens in the early years of life. Together, our findings provide evidence for BALT as an early life adaptation for mobilizing localized immune protection to the diverse respiratory challenges during this formative life stage.
Infants require coordinated immune responses to prevent succumbing to multiple infectious challenges during early life, particularly in the respiratory tract. The mechanisms by which infant T cells ...are functionally adapted for these responses are not well understood. Here, we demonstrated using an in vivo mouse cotransfer model that infant T cells generated greater numbers of lung-homing effector cells in response to influenza infection compared with adult T cells in the same host, due to augmented T cell receptor (TCR)–mediated signaling. Mouse infant T cells showed increased sensitivity to low antigen doses, originating at the interface between T cells and antigen-bearing accessory cells—through actin-mediated mobilization of signaling molecules to the immune synapse. This enhanced signaling was also observed in human infant versus adult T cells. Our findings provide a mechanism for how infants control pathogen load and dissemination, which is important for designing developmentally targeted strategies for promoting immune responses at this vulnerable life stage.
Abstract
Infants are highly susceptible to respiratory infections and frequently experience recurrent episodes. Our previous study demonstrated that tissue resident memory T cells (TRM), which are ...critical in mediating long-term protection against pathogens, are reduced in infant mice compared to adult mice after influenza infection. However, the underlying mechanisms for reduced TRM generation in infants is still unknown. Our preliminary data show that infant T cells have enhanced TCR sensitivity leading to increased activation compared to adult T cells and thus are biased towards effector differentiation at the expense of memory formation. We show that infant OVA-specific (OTII) T cells exhibit lower T cell activation threshold for proliferation and enhanced sensitivity for low does of antigen. Infant T cells express higher levels of CD69 and CD25 with a greater induction of Nur77, a direct indicator of TCR signal strength, at peptide doses that fail to fully activate adult T cells. Co-transfer of infant and adult OTII T cells into a congenic host resulted in infant T cells dominating the effector response in the lungs (at a ratio of 3:1) after primary influenza challenge. At the peak of infection, infant effector T cells also expressed lower levels of TCF1 and Bcl-2, indicating transcriptional bias for terminal effector differentiation with reduced survival. Moreover, infant derived effector and memory T cells express lower levels of CD5, suggesting enhanced survival of lower affinity T cells after influenza infection. Taken together, these results show that enhanced sensitivity for antigenic stimulation promotes cell intrinsic mechanisms that govern decreased potential of infants to form durable and functional lung TRM.
Abstract
γδT cells are unconventional T lymphocytes which seed peripheral tissues in early life. They provide frontline anti-pathogen, anti-cancer and homeostatic responses, rapidly initiated in ...response to signals of cellular stress independent of MHC-recognition. However, the role of γδT cells in humans has been difficult to assess given their purported tissue residency. Using tissues obtained from organ donors, we conducted flow cytometry, TCR-sequencing, and stimulation assays on γδT cells isolated from blood, spleen, lung, intestines and lymph nodes (LN) to create an ‘atlas’ across the human body throughout life. γδT cells were enriched in the blood, spleen, lung, and jejunum in early life, whereas LN proportions were maintained at low levels. Vδ1 and Vδ2 γδT cell subsets also exhibited tissue- and age-specific phenotypes: Vδ1 cells predominated in all organs in infancy except the lung. They were ‘naïve-like’, acquiring a mature phenotype with age, whereas Vδ2 possessed an effector memory signature, even in donors a few days old. Functionally, Vδ2 cells produced IFNγ, TNFα, GzmB and perforin at high levels in childhood. By contrast, Vδ1 cells favored Areg production during infancy but acquired a cytotoxic profile into adulthood. TCR analysis revealed clonal expansion in mucosal organs, whereas lymphoid sites had increased diversity in early life. Despite this site-specific clonal expansion, V-chain usage was stably distributed across organs and did not show the tissue-specific biases seen in mice. Our analyses reveal that γδT cells may play an outsized role in pediatric tissue immune responses and identify potentially divergent roles of specific subsets that contribute to tissue immunity during the most vulnerable years of life.
Abstract
Protection from viral respiratory tract infections (VRTIs) is dependent on the activation, differentiation, and maintenance of antigen specific memory T cells. Iron is essential for ...fundamental metabolic processes in the human body, with iron deficiency, the most prevalent micronutrient deficiency worldwide, resulting in increased morbidity and mortality to VRTIs. The role of iron in the establishment and maintenance of memory T cells is not fully defined. Using a murine model of dietary iron modulation, we define the impact of iron deficiency on anti-viral T cell memory formation, functionality, and resultant protection during primary and heterosubtypic influenza infections. Multi-parameter flow cytometry and stimulation assays were performed on T cells isolated from lung and spleen at effector and memory time points following primary (X31) infection, as well as 5 days post heterosubtypic (PR8) challenge. Strikingly, there was no significant difference in the numbers or proportions of CD4+ and CD8+ influenza specific memory T-cells at any time point when comparing iron deficient to iron replete mice. However, memory T cells generated by iron deficient mice displayed impaired production of key effector cytokines, most notably IFN-γ and IL-17a. Importantly, following heterosubtypic challenge, iron deficient mice exhibited increased morbidity, as defined by increased weight loss, and significantly diminished IFN-γ production by T cells across all sites. This work reveals that distinct iron profiles did not interfere with the generation or maintenance of influenza specific T cells but iron deficiency significantly impacts memory T cell anti-viral functionality resulting in impaired protective responses.
Supported by -K23 AI141686 -UL1 TR001873
Abstract
Memory T cells are essential for optimal protection from previously encountered pathogens. Immune responses in infants lack the benefit of memory and are intrinsically distinct from those in ...adults. Early life adaptive immune responses have been characterized by increased generation of terminal effector subsets with decreased production of long lived memory. Here we investigate the origin of memory T cells utilizing flow cytometry and immunohistochemistry to characterize proportions and localization of T cell subsets in mucosal (intestine/lung) tissue from infant organ donors (n=12). At birth lung T cells are predominantly naïve and localized to the interstitium of the airways with memory accumulating over the first year of life. In contrast, significant proportions of memory phenotype T cells can be found in the lamina propria and intraepithelial layer of the intestine shortly after birth along with naïve cells. Effector memory subsets could be detected in robust proportions, highest in the jejunum, from 3 organ donors all less than 8 days of age. Additionally these memory T cells displayed high levels of canonical resident memory markers (CD69 and CD103). We conclude that mucosal tissues are host to naïve cells which cannot be attributable to circulating populations and that memory subsets are generated within these mucosal sites early in life. Importantly T cells in the youngest donors (ages 0–8 days) displayed resident memory phenotypes raising the possibility of prenatal development of adaptive memory responses populating the intestine. These results warrant additional investigation to determine the persistence and functionality of these subsets and emphasize the importance of the intestine to early life adaptive immunity.
We systematically generated large-scale data sets to improve genome annotation for the nematode Caenorhabditis elegans, a key model organism. These data sets include transcriptome profiling across a ...developmental time course, genome-wide identification of transcription factor-binding sites, and maps of chromatin organization. From this, we created more complete and accurate gene models, including alternative splice forms and candidate noncoding RNAs. We constructed hierarchical networks of transcription factor-binding and microRNA interactions and discovered chromosomal locations bound by an unusually large number of transcription factors. Different patterns of chromatin composition and histone modification were revealed between chromosome arms and centers, with similarly prominent differences between autosomes and the X chromosome. Integrating data types, we built statistical models relating chromatin, transcription factor binding, and gene expression. Overall, our analyses ascribed putative functions to most of the conserved genome.
Abstract
Early life susceptibility to respiratory pathogens is well established in infants and young children, however the specific adaptations of the infant immune system for responding to multiple ...respiratory challenges are not known. Here, we examined lung and lung-associated lymph nodes derived from infant and pediatric organ donors (0–13 years) by confocal immunofluorescence and high dimensional flow cytometry. We identified early formation of bronchial associated lymphoid tissue (BALT) where active immune responses are initiated. At 8 days of life, few immune cells were present around the airways. By 5 months old, we start to observe BALT formation. However, BALT lose their structure with aging and are mostly absent by 10 years of age with CD4 memory T cells dominating the population around the central airways. Germinal centers are seen in 50–60% of BALT during the first two years of life. The percentage of BALT with germinal centers decreases over age, while germinal center formation in lung lymph nodes is maintained throughout infancy and childhood. Flow cytometry data shows seeding of transitional and immature B cells in the lung during infancy, which decreases over age. However, proportion of IgG and IgA memory B cells increases significantly over age both in the lung and lung lymph nodes. The frequency of naïve B cells is stable throughout childhood in both sites. Our results suggest that localized tertiary lymphoid structures in pediatric lungs may be an important mechanism for mobilizing rapid in situ protection during the first few years of life when memory T cells and B cells are not fully established.
Supported by grants listed below: “Human Atlas of Neonatal Development and Early Life-Immunity (HANDEL-I)”(award Number 2018PG-T1D071 The Leona M. and Harry B. Helmsley Charitable Trust) “Immunobiology and alveolar physiology of the aging lung” (U01 HL145547, NIH/NHLBI )
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