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Lymph nodes (LNs) are strategically positioned at dedicated sites throughout the body to facilitate rapid and efficient immunity. Central to the structural integrity and framework of LNs, and the recruitment and positioning of leukocytes therein, are mesenchymal and endothelial lymph node stromal cells (LNSCs). Advances in the last decade have expanded our understanding and appreciation of LNSC heterogeneity, and the role they play in coordinating immunity has grown rapidly. In this review, we will highlight the functional contributions of distinct stromal cell populations during LN development in maintaining immune homeostasis and tolerance and in the activation and control of immune responses. Turley and Krishnamurty review new insights into lymph node stromal cells, a heterogeneous cell population that serves distinct functions during development, in maintaining lymphocyte homeostasis, and in coordinating immune responses.

Fibroblastic reticular cells (FRCs) are specialized stromal cells that define tissue architecture and regulate lymphocyte compartmentalization, homeostasis, and innate and adaptive immunity in secondary lymphoid organs (SLOs). In the present study, we used single-cell RNA sequencing (scRNA-seq) of human and mouse lymph nodes (LNs) to identify a subset of T cell–zone FRCs defined by the expression of Gremlin1 ( Grem1 ) in both species. Grem1 -CreER T2 knock-in mice enabled localization, multi-omics characterization and genetic depletion of Grem1 + FRCs. Grem1 + FRCs primarily localize at T–B cell junctions of SLOs, neighboring pre-dendritic cells and conventional dendritic cells (cDCs). As such, their depletion resulted in preferential loss and decreased homeostatic proliferation and survival of resident cDCs and compromised T cell immunity. Trajectory analysis of human LN scRNA-seq data revealed expression similarities to murine FRCs, with GREM1 + cells marking the endpoint of both trajectories. These findings illuminate a new Grem1 + fibroblastic niche in LNs that functions to maintain the homeostasis of lymphoid tissue-resident cDCs. Fibroblastic reticular cells (FRCs) provide structural support and soluble factors necessary for proper lymph node organization and function. Turley and colleagues use scRNA-seq to identify a unique Gremlin1-expressing FRC subset that is found in T cell zones. Grem1 + FRCs support the survival of resident cDCs and are necessary to promote T cell immunity.

Dendritic cells (DCs) can be viewed as translators between innate and adaptive immunity. They integrate signals derived from tissue infection or damage and present processed antigen from these sites to naive T cells in secondary lymphoid organs while also providing multiple soluble and surface-bound signals that help to guide T cell differentiation. DC-mediated tailoring of the appropriate T cell programme ensures a proper cascade of immune responses that adequately targets the insult. Recent advances in our understanding of the different types of DC subsets along with the cellular organization and orchestration of DC and lymphocyte positioning in secondary lymphoid organs over time has led to a clearer understanding of how the nature of the T cell response is shaped. This Review discusses how geographical organization and ordered sequences of cellular interactions in lymph nodes and the spleen regulate immunity.

The effects on the ontogeny of serum cytokines and immune cells caused by feeding suckling piglets with sow/gilt colostrum and milk replacer was assessed in the present study. After farrowing, the piglets born were randomized into six groups: GG and SS (n = 10/group): piglets were kept with their dam; GS (n = 10): piglets were changed from gilts to sows; SG (n = 10): piglets were changed from sows to gilts; GMR (n = 6) and SMR (n = 8): piglets from either gilts or sows were isolated from the dams and were bottle-fed ad libitum with commercial formula milk replacer. The piglets remained in the groups during the first 24 h of life and were later returned to their respective mothers. Serum immunoglobulin concentration and lymphocyte proliferation from the blood, spleen, thymus, and mesenteric lymph node of the piglets were assessed at 24 h and at 28 days of age. Serum cytokine concentrations were measured through a cytokine multiplex assay at 24 h. Overall, piglets suckling on sows (SS and GS) had a higher concentration of serum immunoglobulin at 24 h, which was also associated with a rise in plasma cytokine concentration and greater ability of B and T cells from lymphatic organs and blood mononuclear cells to respond to mitogens. We suggest a bias towards Th1-, Th2-, and Th17-cell polarizing and cytokines during the suckling period, which may be influenced by maternal immunological factors in the colostrum, such as dam parity. All findings suggest sow parity having a possible role, which may contribute to exerting a modulating action on immune response development.

Although much is known about the physiological framework of T cell motility, and numerous rate-limiting molecules have been identified through loss-of-function approaches, an integrated functional concept of T cell motility is lacking. Here, we used in vivo precision morphometry together with analysis of cytoskeletal dynamics in vitro to deconstruct the basic mechanisms of T cell migration within lymphatic organs. We show that the contributions of the integrin LFA-1 and the chemokine receptor CCR7 are complementary rather than positioned in a linear pathway, as they are during leukocyte extravasation from the blood vasculature. Our data demonstrate that CCR7 controls cortical actin flows, whereas integrins mediate substrate friction that is sufficient to drive locomotion in the absence of considerable surface adhesions and plasma membrane flux. Sixt, Stein and colleagues show that during T cell migration within lymphatic organs, the chemokine receptor CCR7 quantitatively controls the speed of a continuous actin flow, which is coupled to the environment by the integrin LFA-1.

T cell lineages are defined by specialized functions and differential expression of surface antigens, cytokines and transcription factors. Conventional CD4+ and CD8+ T cells are the best studied of the T cell subsets, but ‘unconventional’ T cells have emerged as being more abundant and influential than has previously been appreciated. Key subsets of unconventional T cells include natural killer T (NKT) cells, mucosal-associated invariant T (MAIT) cells and γδ T cells; collectively, these make up ~10% of circulating T cells, and often they are the majority of T cells in tissues such as the liver and gut mucosa. Defects and deficiencies in unconventional T cells are associated with autoimmunity, chronic inflammation and cancer, so it is important to understand how their development is regulated. In this Review, we describe the thymic development of NKT cells, MAIT cells and γδ T cells and highlight some of the key differences between conventional and unconventional T cell development.The authors compare the thymic development of several innate-like T cell populations, including natural killer T cells, mucosal-associated invariant T cells and γδ T cells. They focus on the cytokines, surface molecules and transcription factors that are necessary for the development of these cells and highlight some of the key differences from conventional T cell development.

The thymus is an evolutionarily conserved organ that supports the development of T cells. Not only does the thymic environment support the rearrangement and expression of diverse T cell receptors but also provides a unique niche for the selection of appropriate T cell clones. Thymic selection ensures that the repertoire of available T cells is both useful (being MHC-restricted) and safe (being self-tolerant). The unique antigen-presentation features of the thymus ensure that the display of self-antigens is optimal to induce tolerance to all types of self-tissue. MHC class-specific functions of CD4+ T helper cells, CD8+ killer T cells and CD4+ regulatory T cells are also established in the thymus. Finally, the thymus provides signals for the development of several minor T cell subsets that promote immune and tissue homeostasis. This Review provides an introductory-level overview of our current understanding of the sophisticated thymic selection mechanisms that ensure T cells are useful and safe.This Review summarizes how the processes of thymic selection together ensure that the T cell repertoire is fully functional and safe. In the thymus, T cell receptor signal strength is integrated with distinct stromal cues to result in positive or negative selection of thymocytes or the generation of regulatory cells.

The skin is the outermost organ of the body and is continuously exposed to external pathogens. Upon inflammation, various immune cells pass through, reside in or are recruited to the skin to orchestrate diverse cutaneous immune responses. To achieve this, immune cells interact with each other and even communicate with non-immune cells, including peripheral nerves and the microbiota. Immunologically important anatomical sites, such as skin appendages (for example, hair follicles and sweat glands) or postcapillary venules, act as special portal sites for immune cells and for establishing tertiary lymphoid structures, including inducible skin-associated lymphoid tissue. Here, we provide an overview of the key findings and concepts of cutaneous immunity in association with skin anatomy and discuss how cutaneous immune cells fine-tune physiological responses in the skin.

Cell differentiation is accurately modeled by an algorithm that orders single cells along branched developmental trajectories. Recent single-cell analysis technologies offer an unprecedented opportunity to elucidate developmental pathways. Here we present Wishbone, an algorithm for positioning single cells along bifurcating developmental trajectories with high resolution. Wishbone uses multi-dimensional single-cell data, such as mass cytometry or RNA-Seq data, as input and orders cells according to their developmental progression, and it pinpoints bifurcation points by labeling each cell as pre-bifurcation or as one of two post-bifurcation cell fates. Using 30-channel mass cytometry data, we show that Wishbone accurately recovers the known stages of T-cell development in the mouse thymus, including the bifurcation point. We also apply the algorithm to mouse myeloid differentiation and demonstrate its generalization to additional lineages. A comparison of Wishbone to diffusion maps, SCUBA and Monocle shows that it outperforms these methods both in the accuracy of ordering cells and in the correct identification of branch points.

Much of our knowledge regarding the interactions between epithelial tissues and the immune system has been gathered from animal models and co-cultures with cell lines. However, unique features of human cells cannot be modelled in mice, and cell lines are often transformed or genetically immortalized. Organoid technology has emerged as a powerful tool to maintain epithelial cells in a near-native state. In this Review, we discuss how organoids are being used in immunological research to understand the role of epithelial cell–immune cell interactions in tissue development and homeostasis, as well as in diseases such as cancer.Organoid technology has emerged as a powerful tool to maintain epithelial cells in a near-native state that can be used to better understand the interactions between epithelial cells and the immune system in tissue development, homeostasis, infection and cancer.