Explore the vast range of titles available.

Human T cells coordinate adaptive immunity in diverse anatomic compartments through production of cytokines and effector molecules, but it is unclear how tissue site influences T cell persistence and function. Here, we use single cell RNA-sequencing (scRNA-seq) to define the heterogeneity of human T cells isolated from lungs, lymph nodes, bone marrow and blood, and their functional responses following stimulation. Through analysis of >50,000 resting and activated T cells, we reveal tissue T cell signatures in mucosal and lymphoid sites, and lineage-specific activation states across all sites including distinct effector states for CD8 + T cells and an interferon-response state for CD4 + T cells. Comparing scRNA-seq profiles of tumor-associated T cells to our dataset reveals predominant activated CD8 + compared to CD4 + T cell states within multiple tumor types. Our results therefore establish a high dimensional reference map of human T cell activation in health for analyzing T cells in disease. Immune cells are shaped by the tissue environment, yet the states of healthy human T cells are mainly studied in the blood. Here, the authors perform single cell RNA-seq of T cells from tissues and blood of healthy donors and show its utility as a reference map for comparison of human T cell states in disease.

Tissue-resident memory T cells (TRM) comprise a newly defined subset, which comprises a major component of lymphocyte populations in diverse peripheral tissue sites, including mucosal tissues, barrier surfaces, and in other non-lymphoid and lymphoid sites in humans and mice. Many studies have focused on the role of CD8 TRM in protection; however, there is now accumulating evidence that CD4 TRM predominate in tissue sites, and are integral for in situ protective immunity, particularly in mucosal sites. New evidence suggests that mucosal CD4 TRM populations differentiate at tissue sites following the recruitment of effector T cells by local inflammation or infection. The resulting TRM populations are enriched in T-cell specificities associated with the inducing pathogen/antigen. This compartmentalization of memory T cells at specific tissue sites may provide an optimal design for future vaccination strategies. In addition, emerging evidence suggests that CD4 TRM may also play a role in immunoregulation and immunopathology, and therefore, targeting TRM may be a viable therapeutic approach to treat inflammatory diseases in mucosal sites. This review will summarize our current understanding of CD4 TRM in diverse tissues, with an emphasis on their role in protective immunity and the mechanisms by which these populations are established and maintained in diverse mucosal sites.

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 (T RM ) 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 T RM clones exhibit site-specific expansions and distinct functional capacities. Together, our findings indicate that circulating T cells are more disseminated and differentiated, while T RM cells exhibit tissue-specific adaptation and clonal segregation, suggesting that strategies to promote barrier immunity require tissue targeting. Farber and colleagues examine the phenotypic, transcriptomic, clonal, and functional differences between tissue-resident T cells in various barrier tissue sites relative to T cells in lymphoid organs and circulation in humans.

Group 2 innate lymphoid cells are shown to have a critical role in energy homeostasis by producing methionine-enkephalin peptides in response to interleukin 33, thus promoting the beiging of white adipose tissue; increased numbers of beige (also known as brown-like or brite) fat cells in white adipose tissue leads to increased energy expenditure and decreased adiposity. Innate lymphoid cells drive energy up, adiposity down The immune system is now thought to be involved in the development of obesity, together with genetic and environmental factors. Recent research identified group 2 innate lymphoid cells (ILC2s) in adipose tissue as a factor in the development of obesity in mice. David Artis and colleagues show here that ILC2s play a critical role in energy homeostasis by producing methionine-enkephalin peptides in response to interleukin-33. This promotes the emergence of beige adipocytes, a specialized adipocyte population arising from white adipose tissue. This 'beiging' process leads to increased energy expenditure and decreased adiposity. Obesity is an increasingly prevalent disease regulated by genetic and environmental factors. Emerging studies indicate that immune cells, including monocytes, granulocytes and lymphocytes, regulate metabolic homeostasis and are dysregulated in obesity 1 , 2 . Group 2 innate lymphoid cells (ILC2s) can regulate adaptive immunity 3 , 4 and eosinophil and alternatively activated macrophage responses 5 , and were recently identified in murine white adipose tissue (WAT) 5 where they may act to limit the development of obesity 6 . However, ILC2s have not been identified in human adipose tissue, and the mechanisms by which ILC2s regulate metabolic homeostasis remain unknown. Here we identify ILC2s in human WAT and demonstrate that decreased ILC2 responses in WAT are a conserved characteristic of obesity in humans and mice. Interleukin (IL)-33 was found to be critical for the maintenance of ILC2s in WAT and in limiting adiposity in mice by increasing caloric expenditure. This was associated with recruitment of uncoupling protein 1 (UCP1) + beige adipocytes in WAT, a process known as beiging or browning that regulates caloric expenditure 7 , 8 , 9 . IL-33-induced beiging was dependent on ILC2s, and IL-33 treatment or transfer of IL-33-elicited ILC2s was sufficient to drive beiging independently of the adaptive immune system, eosinophils or IL-4 receptor signalling. We found that ILC2s produce methionine-enkephalin peptides that can act directly on adipocytes to upregulate Ucp1 expression in vitro and that promote beiging in vivo . Collectively, these studies indicate that, in addition to responding to infection or tissue damage, ILC2s can regulate adipose function and metabolic homeostasis in part via production of enkephalin peptides that elicit beiging.

Memory B cells (MBCs) protect the body from recurring infections. MBCs differ from their naive counterparts (NBCs) in many ways, but functional and surface marker differences are poorly characterized. In addition, although mice are the prevalent model for human immunology, information is limited concerning the nature of homology in B cell compartments. To address this, we undertook an unbiased, large-scale screening of both human and mouse MBCs for their differential expression of surface markers. By correlating the expression of such markers with extensive panels of known markers in high-dimensional flow cytometry, we comprehensively identified numerous surface proteins that are differentially expressed between MBCs and NBCs. The combination of these markers allows for the identification of MBCs in humans and mice and provides insight into their functional differences. These results will greatly enhance understanding of humoral immunity and can be used to improve immune monitoring.Weisel and colleagues provide a resource that phenotypically profiles naive and memory B cells and provides a comparative analysis of memory B cells found in humans versus mice.

By contrast, the corresponding blood samples were low in T cells, but high in other immune cells called monocytes, which were displaying unusual patterns of cell-surface receptors. Mouse studies have also shown that, for site-specific viruses such as influenza or human papillomavirus, immunological memory is maintained by dedicated sets of memory T cells at the relevant site. After clinical teams obtain the person's organs for transplantation, our surgeon collects tissues for research - including the intestines, lungs, many lymph nodes, the thymus, spleen, bone marrow, skin, tonsils and salivary glands - and brings everything directly back to the laboratory for processing and sample storage. Technological advances mean that RNA transcripts, protein content and gene modifications can be pinpointed even for single cells.

B-cell VH region repertoire sequencing of eight anatomical sites in six human donors reveals distinct networks of clone distribution. B-cell responses result in clonal expansion, and can occur in a variety of tissues. To define how B-cell clones are distributed in the body, we sequenced 933,427 B-cell clonal lineages and mapped them to eight different anatomic compartments in six human organ donors. We show that large B-cell clones partition into two broad networks—one spans the blood, bone marrow, spleen and lung, while the other is restricted to tissues within the gastrointestinal (GI) tract (jejunum, ileum and colon). Notably, GI tract clones display extensive sharing of sequence variants among different portions of the tract and have higher frequencies of somatic hypermutation, suggesting extensive and serial rounds of clonal expansion and selection. Our findings provide an anatomic atlas of B-cell clonal lineages, their properties and tissue connections. This resource serves as a foundation for studies of tissue-based immunity, including vaccine responses, infections, autoimmunity and cancer.

COVID has shown we must study immunity in the whole body — let’s sort the logistics to acquire the right samples. COVID has shown we must study immunity in the whole body — let’s sort the logistics to acquire the right samples.

The new vaccines against SARS-CoV-2 are novel in terms of specificity, their wide dissemination across the global population and the inclusion of newly licensed mRNA platforms. We discuss here how the approved vaccines trigger innate immunity to promote durable immunological memory and consider the future implications of protecting populations with these vaccines.This Comment outlines how the recently licensed vaccines for COVID-19 activate innate immune mechanisms to promote immune memory to SARS-CoV-2. The authors also consider future challenges that could limit vaccine efficacy.

Lung fibrosis is increasingly detected with aging and has been associated with poor outcomes in acute lung injury or infection. However, the molecular programs driving this pro-fibrotic evolution are unclear. Here we profile distal lung samples from healthy human donors across the lifespan. Gene expression profiling by bulk RNAseq reveals both increasing cellular senescence and pro-fibrotic pathway activation with age. Quantitation of telomere length shows progressive shortening with age, which is associated with DNA damage foci and cellular senescence. Cell type deconvolution analysis of the RNAseq data indicates a progressive loss of lung epithelial cells and an increasing proportion of fibroblasts with age. Consistent with this pro-fibrotic profile, second harmonic imaging of aged lungs demonstrates increased density of interstitial collagen as well as decreased alveolar expansion and surfactant secretion. In this work, we reveal the transcriptional and structural features of fibrosis and associated functional impairment in normal lung aging. Age is associated with increasing vulnerability to both acute and chronic lung diseases. Employing genomic analysis and live lung imaging, this study reveals a profile of increased cellular senescence, telomere shortening, and fibrosis-induced impaired alveolar function in the natural history of human lung aging.