Explore the vast range of titles available.

The discovery of innate lymphoid cells (ILCs) has revolutionized our understanding of innate immunity and immune cell interactions at epithelial barrier sites. Their presence and maintenance are critical for modulating immune homeostasis, responding to injury or infection, and repairing damaged tissues. To date, ILCs have been defined by a set of transcription factors, surface antigens and cytokines, and their functions resemble those of three major classes of helper T cell subsets, Th1, Th2 and Th17. Despite this, the lack of antigen-specific surface receptors and the notion that ILCs can develop in the absence of the thymic niche have clearly set them apart from the T-cell lineage and promulgated a dogma that ILCs develop directly from progenitors in the bone marrow. Interestingly however, emerging studies have challenged the BM-centric view of adult ILC development and suggest that ILCs could arise neonatally from developing T cell progenitors. In this review, we discuss ILC development in parallel to T-cell development and summarize key findings that support a T-cell-centric view of ILC ontogeny.

We aimed at identifying the developmental stage at which leukemic cells of pediatric T‐ALLs are arrested and at defining leukemogenic mechanisms based on ATAC‐Seq. Chromatin accessibility maps of seven developmental stages of human healthy T cells revealed progressive chromatin condensation during T‐cell maturation. Developmental stages were distinguished by 2,823 signature chromatin regions with 95% accuracy. Open chromatin surrounding SAE1 was identified to best distinguish thymic developmental stages suggesting a potential role of SUMOylation in T‐cell development. Deconvolution using signature regions revealed that T‐ALLs, including those with mature immunophenotypes, resemble the most immature populations, which was confirmed by TF‐binding motif profiles. We integrated ATAC‐Seq and RNA‐Seq and found DAB1 , a gene not related to leukemia previously, to be overexpressed, abnormally spliced and hyper‐accessible in T‐ALLs. DAB1 ‐negative patients formed a distinct subgroup with particularly immature chromatin profiles and hyper‐accessible binding sites for SPI1 ( PU.1 ), a TF crucial for normal T‐cell maturation. In conclusion, our analyses of chromatin accessibility and TF‐binding motifs showed that pediatric T‐ALL cells are most similar to immature thymic precursors, indicating an early developmental arrest. Synopsis Analysis of chromatin accessibility of human T‐cell precursors revealed progressive chromatin condensation during maturation. Pediatric T‐ALLs resemble the most immature populations indicating that the epigenetic landscape of this type of leukemia is most similar to the earliest thymic precursors. The chromatin of differentiating human thymocytes becomes gradually condensed during maturation. Human T‐cell differentiation leaves a detectable signature in genome‐wide chromatin accessibility, which can be used to predict thymocyte maturation stage. The chromatin architecture and TF binding motif accessibility of pediatric T‐ALLs exhibit the highest resemblance to the most immature thymic precursors. Integration of ATAC‐Seq and RNA‐Seq identifies differentially accessible and expressed genes in T‐cell leukemias in comparison to healthy T‐cell precursors. Pediatric T‐ALLs either exhibit hyper‐accessibility of DAB1 overexpressing an atypical isoform, or hyper‐accessibility of SPI1(PU.1) binding motifs as well as SPI1 overexpression. Graphical Abstract Analysis of chromatin accessibility of human T‐cell precursors revealed progressive chromatin condensation during maturation. Pediatric T‐ALLs resemble the most immature populations indicating that the epigenetic landscape of this type of leukemia is most similar to the earliest thymic precursors.

The E/ID protein axis is instrumental for defining the developmental progression and functions of hematopoietic cells. The E proteins are dimeric transcription factors that activate gene expression programs and coordinate changes in chromatin organization. Id proteins are antagonists of E protein activity. Relative levels of E/Id proteins are modulated throughout hematopoietic development to enable the progression of hematopoietic stem cells into multiple adaptive and innate immune lineages including natural killer cells, B cells and T cells. In early progenitors, the E proteins promote commitment to the T and B cell lineages by orchestrating lineage specific programs of gene expression and regulating VDJ recombination of antigen receptor loci. In mature B cells, the E/Id protein axis functions to promote class switch recombination and somatic hypermutation. E protein activity further regulates differentiation into distinct CD4+ and CD8+ T cells subsets and instructs mature T cell immune responses. In this review, we discuss how the E/Id proteins define the adaptive immune system lineages, focusing on their role in directing developmental gene programs.

The concept of clonal deletion of immune cells that carry an autoreactive antigen receptor was a central prediction of Burnet's clonal selection theory. A series of classical experiments in the late 1980s revealed that certain immature thymocytes upon encounter of ‘self’ are indeed removed from the T‐cell repertoire before their release into the blood circulation. A second essential cornerstone of immunological tolerance, not anticipated by Burnett, has more recently surfaced through the discovery of Foxp3+ regulatory T cells (Treg). Intriguingly, it appears that the expression of an autoreactive T‐cell receptor is a shared characteristic of T cells that are subject to clonal deletion as well as of those deviated into the Treg lineage. This is all the more striking as Treg differentiation for the most part branches off from mainstream CD4T cell development during thymocyte maturation in the thymus, that is, it may neither temporally nor spatially be separated from clonal deletion. This raises the question of how an apparently identical stimulus, namely the encounter of ‘self’ during thymocyte development, can elicit fundamentally different outcomes such as apoptotic cell death on the one hand or differentiation into a highly specialized T‐cell lineage on the other hand. Here, we will review the T‐cell intrinsic and extrinsic factors that have been implicated in intrathymic Treg differentiation and discuss how these parameters may determine whether an autoreactive major histocompatibility complex class II‐restricted thymocyte is deviated into the Treg lineage or subject to clonal deletion.

The role of the immunoproteasome is perceived as confined to adaptive immune responses given its ability to produce peptides ideal for MHC Class‐I binding. Here, we demonstrate that the immunoproteasome subunit, LMP2, has functions beyond its immunomodulatory role. Using LMP2‐deficient mice, we demonstrate that LMP2 is crucial for lymphocyte development and survival in the periphery. Moreover, LMP2‐deficient lymphocytes show impaired degradation of key BH3‐only proteins, resulting in elevated levels of pro‐apoptotic BIM and increased cell death. Interestingly, LMP2 is the sole immunoproteasome subunit required for BIM degradation. Together, our results suggest LMP2 has important housekeeping functions and represents a viable therapeutic target for cancer. We demonstrated that proteasomes incorporating the LMP2 subunit are required for pro‐apoptotic molecule BIM degradation. In the absence of LMP2, lymphocytes in the thymus and in the periphery have significant survival issues.

CD4 + helper and CD8 + cytotoxic T cells differentiate from common precursors in the thymus after T‐cell receptor (TCR)‐mediated selection. Commitment to the helper lineage depends on persistent TCR signals and expression of the ThPOK transcription factor, whereas a ThPOK cis‐regulatory element, ThPOK silencer, represses Thpok gene expression during commitment to the cytotoxic lineage. Here, we show that silencer‐mediated alterations of chromatin structures in cytotoxic‐lineage thymocytes establish a repressive state that is epigenetically inherited in peripheral CD8 + T cells even after removal of the silencer. When silencer activity is enhanced in helper‐lineage cells, by increasing its copy number, a similar heritable Thpok silencing occurs. Epigenetic locking of the Thpok locus may therefore be an independent event from commitment to the cytotoxic lineage. These findings imply that long‐lasting TCR signals are needed to establish stable Thpok expression activity to commit to helper T‐cell fate and that full commitment to the helper lineage requires persistent reversal of silencer activity during a particular time window. Persistent TCR signalling during thymocyte lineage commitment prevents epigenetic silencing of the transcription factor ThPOK locus; stable Thpok expression leads to CD4+ helper cell fate commitment.

The lifelong generation of αβT cells enables us to continuously build immunity against pathogens and malignancies despite the loss of thymic function with age. Homeostatic proliferation of post-thymic naïve and memory T cells and their transition into effector and long-lived memory cells balance the decreasing output of naïve T cells, and recent research suggests that also αβT-cell development independent from the thymus may occur. However, the sites and mechanisms of extrathymic T-cell development are not yet understood in detail. γδT cells represent a small fraction of the overall T-cell pool, and are endowed with tremendous phenotypic and functional plasticity. γδT cells that express the Vδ1 gene segment are a minor population in human peripheral blood but predominate in epithelial (and inflamed) tissues. Here, we characterize a CD4(+) peripheral Vδ1(+) γδT-cell subpopulation that expresses stem-cell and progenitor markers and is able to develop into functional αβT cells ex vivo in a simple culture system and in vivo. The route taken by this process resembles thymic T-cell development. However, it involves the re-organization of the Vδ1(+) γδTCR into the αβTCR as a consequence of TCR-γ chain downregulation and the expression of surface Vδ1(+)Vβ(+) TCR components, which we believe function as surrogate pre-TCR. This transdifferentiation process is readily detectable in vivo in inflamed tissue. Our study provides a conceptual framework for extrathymic T-cell development and opens up a new vista in immunology that requires adaptive immune responses in infection, autoimmunity, and cancer to be reconsidered.

Histone deacetylase 7 (HDAC7) is a T‐cell receptor (TCR) signal‐dependent regulator of differentiation that is highly expressed in CD4/CD8 double‐positive (DP) thymocytes. Here, we examine the effect of blocking TCR‐dependent nuclear export of HDAC7 during thymic selection, through expression of a signal‐resistant mutant of HDAC7 (HDAC7‐ΔP) in thymocytes. We find that HDAC7‐ΔP transgenic thymocytes exhibit a profound block in negative thymic selection, but can still undergo positive selection, resulting in the escape of autoreactive T cells into the periphery. Gene expression profiling reveals a comprehensive suppression of the negative selection‐associated gene expression programme in DP thymocytes, associated with a defect in the activation of MAP kinase pathways by TCR signals. The consequence of this block in vivo is a lethal autoimmune syndrome involving the exocrine pancreas and other abdominal organs. These experiments establish a novel molecular model of autoimmunity and cast new light on the relationship between thymic selection and immune self‐tolerance. Histone deacetylase 7 (HDAC7) maintains immunological self‐tolerance by acting as a T‐cell receptor regulated gatekeeper of the genetic programme that mediates negative thymic selection.

The development and differentiation of T cells represents a long and highly coordinated, yet flexible at some points, pathway, along which the sequential and dynamic expressions of different transcriptional factors play prominent roles at multiple steps. The large ZBTB family comprises a diverse group of transcriptional factors, and many of them have emerged as critical factors that regulate the lineage commitment, differentiation and effector function of hematopoietic-derived cells as well as a variety of other developmental events. Within the T-cell lineage, several ZBTB proteins, including ZBTB1, ZBTB17, ZBTB7B (THPOK) and BCL6 (ZBTB27), mainly regulate the development and/or differentiation of conventional CD4/CD8 αβ + T cells, whereas ZBTB16 (PLZF) is essential for the development and function of innate-like unconventional γ δ + T & invariant NKT cells. Given the critical role of T cells in host defenses against infections/tumors and in the pathogenesis of many inflammatory disorders, we herein summarize the roles of fourteen ZBTB family members in the development, differentiation and effector function of both conventional and unconventional T cells as well as the underlying molecular mechanisms.

Conventional T cell fate and function are determined by coordination between cellular signaling and mitochondrial metabolism. Invariant natural killer T (iNKT) cells are an important subset of “innate-like” T cells that exist in a preactivated effector state, and their dependence on mitochondrial metabolism has not been previously defined genetically or in vivo. Here, we show that mature iNKT cells have reduced mitochondrial respiratory reserve and iNKT cell development was highly sensitive to perturbation of mitochondrial function. Mice with T cell-specific ablation of Rieske iron-sulfur protein (RISP; T-Uqcrfs1 −/−), an essential subunit of mitochondrial complex III, had a dramatic reduction of iNKT cells in the thymus and periphery, but no significant perturbation on the development of conventional T cells. The impaired development observed in T-Uqcrfs1 −/− mice stems from a cell-autonomous defect in iNKT cells, resulting in a differentiation block at the early stages of iNKT cell development. Residual iNKT cells in T-Uqcrfs1 −/− mice displayed increased apoptosis but retained the ability to proliferate in vivo, suggesting that their bioenergetic and biosynthetic demands were not compromised. However, they exhibited reduced expression of activation markers, decreased T cell receptor (TCR) signaling and impaired responses to TCR and interleukin-15 stimulation. Furthermore, knocking down RISP in mature iNKT cells diminished their cytokine production, correlating with reduced NFATc2 activity. Collectively, our data provide evidence for a critical role of mitochondrial metabolism in iNKT cell development and activation outside of its traditional role in supporting cellular bioenergetic demands.