RESUMO
T lymphocytes migrate to barrier sites after exposure to pathogens, providing localized immunity and long-term protection. Here, we obtained blood and tissues from human organ donors to examine T cells across major barrier sites (skin, lung, jejunum), associated lymph nodes, lymphoid organs (spleen, bone marrow), and in circulation. By integrating single-cell protein and transcriptome profiling, we demonstrate that human barrier sites contain tissue-resident memory T (TRM) cells that exhibit site-adapted profiles for residency, homing and function distinct from circulating memory T cells. Incorporating T cell receptor and transcriptome analysis, we show that circulating memory T cells are highly expanded, display extensive overlap between sites and exhibit effector and cytolytic functional profiles, while TRM clones exhibit site-specific expansions and distinct functional capacities. Together, our findings indicate that circulating T cells are more disseminated and differentiated, while TRM cells exhibit tissue-specific adaptation and clonal segregation, suggesting that strategies to promote barrier immunity require tissue targeting.
Assuntos
Memória Imunológica , Células T de Memória , Humanos , Linfonodos , Células Clonais , Diferenciação Celular , Linfócitos T CD8-PositivosRESUMO
Infancy and childhood are critical life stages for generating immune memory to protect against pathogens; however, the timing, location, and pathways for memory development in humans remain elusive. Here, we investigated T cells in mucosal sites, lymphoid tissues, and blood from 96 pediatric donors aged 0-10 years using phenotypic, functional, and transcriptomic profiling. Our results revealed that memory T cells preferentially localized in the intestines and lungs during infancy and accumulated more rapidly in mucosal sites compared with blood and lymphoid organs, consistent with site-specific antigen exposure. Early life mucosal memory T cells exhibit distinct functional capacities and stem-like transcriptional profiles. In later childhood, they progressively adopt proinflammatory functions and tissue-resident signatures, coincident with increased T cell receptor (TCR) clonal expansion in mucosal and lymphoid sites. Together, our findings identify staged development of memory T cells targeted to tissues during the formative years, informing how we might promote and monitor immunity in children.
Assuntos
Tecido Linfoide , Células T de Memória , Criança , Humanos , Lactente , Linfócitos T CD8-Positivos , Memória Imunológica , Tecido Linfoide/metabolismo , Mucosa , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Recém-Nascido , Pré-EscolarRESUMO
Immune response dynamics in coronavirus disease 2019 (COVID-19) and their severe manifestations have largely been studied in circulation. Here, we examined the relationship between immune processes in the respiratory tract and circulation through longitudinal phenotypic, transcriptomic, and cytokine profiling of paired airway and blood samples from patients with severe COVID-19 relative to heathy controls. In COVID-19 airways, T cells exhibited activated, tissue-resident, and protective profiles; higher T cell frequencies correlated with survival and younger age. Myeloid cells in COVID-19 airways featured hyperinflammatory signatures, and higher frequencies of these cells correlated with mortality and older age. In COVID-19 blood, aberrant CD163+ monocytes predominated over conventional monocytes, and were found in corresponding airway samples and in damaged alveoli. High levels of myeloid chemoattractants in airways suggest recruitment of these cells through a CCL2-CCR2 chemokine axis. Our findings provide insights into immune processes driving COVID-19 lung pathology with therapeutic implications for targeting inflammation in the respiratory tract.
Assuntos
COVID-19/imunologia , Pulmão/imunologia , Células Mieloides/imunologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , COVID-19/sangue , COVID-19/mortalidade , COVID-19/patologia , Citocinas/imunologia , Citocinas/metabolismo , Humanos , Inflamação , Estudos Longitudinais , Pulmão/patologia , Macrófagos/imunologia , Macrófagos/patologia , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/patologia , Células Mieloides/patologia , SARS-CoV-2 , Linfócitos T/imunologia , Linfócitos T/patologia , Transcriptoma , Adulto JovemRESUMO
Older people are particularly susceptible to infectious and neoplastic diseases of the lung and it is unclear how lifelong exposure to environmental pollutants affects respiratory immune function. In an analysis of human lymph nodes (LNs) from 84 organ donors aged 11-93 years, we found a specific age-related decline in lung-associated, but not gut-associated, LN immune function linked to the accumulation of inhaled atmospheric particulate matter. Increasing densities of particulates were found in lung-associated LNs with age, but not in the corresponding gut-associated LNs. Particulates were specifically contained within CD68+CD169- macrophages, which exhibited decreased activation, phagocytic capacity, and altered cytokine production compared with non-particulate-containing macrophages. The structures of B cell follicles and lymphatic drainage were also disrupted in lung-associated LNs with particulates. Our results reveal that the cumulative effects of environmental exposure and age may compromise immune surveillance of the lung via direct effects on immune cell function and lymphoid architecture.
Assuntos
Pulmão , Linfonodos , Humanos , Idoso , Linfonodos/patologia , Suscetibilidade a Doenças/patologia , Poeira , ImunidadeRESUMO
Maintaining virus-specific adaptive immunity is critical for ongoing protection against SARS-CoV-2 infection. In this issue, Breton et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20202515) identify polyfunctional SARS-CoV-2-specific T cell responses in the peripheral blood of individuals who recovered from COVID-19 that were present at 1 mo and persisted until 6 mo after infection.
Assuntos
COVID-19 , SARS-CoV-2 , Humanos , Imunidade Celular , Linfócitos TRESUMO
The persistence of anti-viral immunity is essential for protection and exhibits profound heterogeneity across individuals. Here, we elucidate the factors that shape maintenance and function of anti-viral T cell immunity in the body by comprehensive profiling of virus-specific T cells across blood, lymphoid organs, and mucosal tissues of organ donors. We use flow cytometry, T cell receptor sequencing, single-cell transcriptomics, and cytokine analysis to profile virus-specific CD8+ T cells recognizing the ubiquitous pathogens influenza and cytomegalovirus. Our results reveal that virus specificity determines overall magnitude, tissue distribution, differentiation, and clonal repertoire of virus-specific T cells. Age and sex influence T cell differentiation and dissemination in tissues, while T cell tissue residence and functionality are highly correlated with the site. Together, our results demonstrate how the covariates of virus, tissue, age, and sex impact the anti-viral immune response, which is important for targeting, monitoring, and predicting immune responses to existing and emerging viruses.
Assuntos
Antivirais/farmacologia , Linfócitos T CD8-Positivos/imunologia , Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Memória Imunológica/imunologia , Vírus da Influenza A/imunologia , Influenza Humana/imunologia , Adulto , Fatores Etários , Criança , Pré-Escolar , Citocinas/metabolismo , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/virologia , Feminino , Humanos , Lactente , Influenza Humana/tratamento farmacológico , Influenza Humana/virologia , Ativação Linfocitária , Masculino , Receptores de Antígenos de Linfócitos T/imunologia , Fatores Sexuais , Análise de Célula Única , TranscriptomaRESUMO
Adaptive immune responses to SARS-CoV-2 infection have been extensively characterized in blood; however, most functions of protective immunity must be accomplished in tissues. Here, we report from examination of SARS-CoV-2 seropositive organ donors (ages 10 to 74) that CD4+ T, CD8+ T, and B cell memory generated in response to infection is present in the bone marrow, spleen, lung, and multiple lymph nodes (LNs) for up to 6 months after infection. Lungs and lung-associated LNs were the most prevalent sites for SARS-CoV-2specific memory T and B cells with significant correlations between circulating and tissue-resident memory T and B cells in all sites. We further identified SARS-CoV-2specific germinal centers in the lung-associated LNs up to 6 months after infection. SARS-CoV-2specific follicular helper T cells were also abundant in lung-associated LNs and lungs. Together, the results indicate local tissue coordination of cellular and humoral immune memory against SARS-CoV-2 for site-specific protection against future infectious challenges.
Assuntos
Anticorpos Antivirais/imunologia , COVID-19/imunologia , Imunidade Celular , Memória Imunológica , Linfócitos/imunologia , SARS-CoV-2/imunologia , Feminino , Humanos , Masculino , Especificidade de Órgãos/imunologiaRESUMO
The human immune system is comprised of a diverse and interactive network of specialized cells localized in diverse tissues throughout the body, where they mediate protection against pathogens and environmental insults while maintaining tissue homeostasis. Although much of our understanding of human immunology has derived from studies of peripheral blood, recent work utilizing human tissue resources and innovative computational methods have employed a whole-body, systems-based approach, revealing tremendous complexity and heterogeneity of the immune system within individuals and across the population. In this review, we discuss how tissue localization, developmental and age-associated changes, and conditions of health and disease shape the immune response, as well as how improved understanding of interindividual and tissue-specific immunity can be leveraged for developing targeted therapeutics.
RESUMO
Immune responses to respiratory viruses like SARS-CoV-2 originate and function in the lung, yet assessments of human immunity are often limited to blood. Here, we conducted longitudinal, high-dimensional profiling of paired airway and blood samples from patients with severe COVID-19, revealing immune processes in the respiratory tract linked to disease pathogenesis. Survival from severe disease was associated with increased CD4 + T cells and decreased monocyte/macrophage frequencies in the airway, but not in blood. Airway T cells and macrophages exhibited tissue-resident phenotypes and activation signatures, including high level expression and secretion of monocyte chemoattractants CCL2 and CCL3 by airway macrophages. By contrast, monocytes in blood expressed the CCL2-receptor CCR2 and aberrant CD163 + and immature phenotypes. Extensive accumulation of CD163 + monocyte/macrophages within alveolar spaces in COVID-19 lung autopsies suggested recruitment from circulation. Our findings provide evidence that COVID-19 pathogenesis is driven by respiratory immunity, and rationale for site-specific treatment and prevention strategies.