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Thymic stromal lymphopoietin (TSLP) is a pleiotropic cytokine that acts on multiple cell lineages, including dendritic cells, T cells, B cells, neutrophils, mast cells, eosinophils and innate lymphoid cells, affecting their maturation, survival and recruitment. It is best known for its role in promoting type 2 immune responses such as in allergic diseases and, in 2021, a monoclonal antibody targeting TSLP was approved for the treatment of severe asthma. However, it is now clear that TSLP has many other important roles in a variety of settings. Indeed, several genetic variants for TSLP are linked to disease severity, and chromosomal alterations in TSLP are common in certain cancers, indicating important roles of TSLP in disease. In this Review, we discuss recent advances in TSLP biology, highlighting how it regulates the tissue environment not only in allergic disease but also in infectious diseases, inflammatory diseases and cancer. Encouragingly, therapies targeting the TSLP pathway are being actively pursued for several diseases.The cytokine thymic stromal lymphopoietin (TSLP) has pleiotropic functions beyond allergic diseases and T helper 2-type immune responses. Here, the authors highlight the roles of TSLP — beneficial or deleterious — in infectious disease, chronic inflammatory disease and cancer by acting on many different cell types.

IL-2 was first identified as a growth factor capable of driving the expansion of activated human T cell populations. In the more than 40 years since its discovery, a tremendous amount has been learned regarding the mechanisms that regulate the expression of both IL-2 and its cell surface receptor, its mechanisms of signalling and its range of biological actions. More recently, the mechanisms by which IL-2 regulates CD4+ T cell differentiation and function have been elucidated. IL-2 also regulates the effector and memory responses of CD8+ T cells, and the loss of IL-2 or responsiveness to IL-2 at least in part explains the exhausted phenotype that occurs during chronic viral infections and in tumour responses. These basic mechanistic studies have led to the therapeutic ability to manipulate the action of IL-2 on regulatory T (Treg) cells for the treatment of autoimmune disease and on CD8+ T cells for immunotherapy of cancer. IL-2 can have either positive or deleterious effects, and we discuss here recent ideas and approaches for manipulating the actions and overall net effects of IL-2 in disease settings, including cancer.

Synthetic receptor signalling has the potential to endow adoptively transferred T cells with new functions that overcome major barriers in the treatment of solid tumours, including the need for conditioning chemotherapy 1 , 2 . Here we designed chimeric receptors that have an orthogonal IL-2 receptor extracellular domain (ECD) fused with the intracellular domain (ICD) of receptors for common γ-chain (γ c ) cytokines IL-4, IL-7, IL-9 and IL-21 such that the orthogonal IL-2 cytokine elicits the corresponding γ c cytokine signal. Of these, T cells that signal through the chimeric orthogonal IL-2Rβ-ECD–IL-9R-ICD (o9R) are distinguished by the concomitant activation of STAT1, STAT3 and STAT5 and assume characteristics of stem cell memory and effector T cells. Compared to o2R T cells, o9R T cells have superior anti-tumour efficacy in two recalcitrant syngeneic mouse solid tumour models of melanoma and pancreatic cancer and are effective even in the absence of conditioning lymphodepletion. Therefore, by repurposing IL-9R signalling using a chimeric orthogonal cytokine receptor, T cells gain new functions, and this results in improved anti-tumour activity for hard-to-treat solid tumours. Synthetic chimeric orthogonal IL-2 receptors that incorporate the intracellular domain of receptors for other γ-chain cytokines such as IL-9 can reroute orthogonal signalling and alter the phenotype of T cells to improve anti-tumour responses.

During T cell differentiation and activation, specific stimuli, and a network of transcription factors (TFs) are involved in orchestrating chromatin accessibility, establishing enhancer-promoter interactions, and regulating gene expression. Over the past few years, there have been new insights into how chromatin interactions coordinate differentiation during T cell development and how regulatory elements are programmed to allow T cells to differentially respond to distinct stimuli. In this review, we discuss recent advances related to the roles of TFs in establishing the regulatory chromatin landscapes that orchestrate T cell development and differentiation. In particular, we focus on the role of TFs (e.g., TCF-1, BCL11B, PU.1, STAT3, STAT5, AP-1, and IRF4) in mediating chromatin accessibility and interactions and in regulating gene expression in T cells, including gene expression that is dependent on IL-2 and IL-21. Furthermore, we discuss the state of knowledge on enhancer-promoter interactions and how autoimmune disease risk variants can be linked to molecular functions of putative target genes.

Interleukin-15 (IL-15) is essential for the development and maintenance of natural killer (NK) cells. IL-15 activates STAT5 proteins, which can form dimers or tetramers. We previously found that NK cell numbers are decreased in Stat5a − Stat5b tetramer-deficient double knockin (DKI) mice, but the mechanism was not investigated. Here we show that STAT5 dimers are sufficient for NK cell development, whereas STAT5 tetramers mediate NK cell maturation and the expression of maturation-associated genes. Unlike the defective proliferation of Stat5 DKI CD8 + T cells, Stat5 DKI NK cells have normal proliferation to IL-15 but are susceptible to death upon cytokine withdrawal, with lower Bcl2 and increased active caspases. These findings underscore the importance of STAT5 tetramers in maintaining NK cell homoeostasis. Moreover, defective STAT5 tetramer formation could represent a cause of NK cell immunodeficiency, and interrupting STAT5 tetramer formation might serve to control NK leukaemia. IL-15 signals through STAT5 to modulate natural killer (NK) cell maturation, function and homeostasis, but the specific contributions of STAT5 dimers and tetramers are still unclear. Here the authors show that, while STAT5 dimers are sufficient for NK development, STAT5 tetramers are essential for NK homoeostasis by modulating apoptosis.

Key Points The receptor for the cytokine interleukin-21 (IL-21) contains the common cytokine-receptor γ-chain, so IL-21 is one of the cytokines that has its effects ablated in individuals with X-linked severe combined immunodeficiency. Although IL-21 is expressed only by CD4 + T cells, its receptor is found at the cell surface of all T cells, B cells, natural killer (NK) cells, dendritic cells (DCs) and keratinocytes, thereby implying that IL-21 has a diverse range of effects. The effects of IL-21 on B cells are context dependent, and they include the induction of apoptosis in naive B cells and, after co-activation with signals from T cells, the induction of differentiation of B cells into plasma cells, through upregulation of expression of B-lymphocyte-induced maturation protein 1 (BLIMP1). IL-21 augments the proliferation of NK cells and leads to the acquisition of a functional cytotoxic state. In vivo treatment with IL-21 leads to increased cytotoxic activity of NK cells and to the induction of a strong antitumour activity in several models of cancer. IL-21 has a synergistic effect on the clonal expansion of CD8 + T cells when delivered in combination with either IL-7 or IL-15. This effect correlates with the ability of IL-21 to promote both increased cytotoxic activity of CD8 + T cells and potent antitumour effects by these cells. IL-21 can negatively control immune responses through its inhibitory effects on DC differentiation and its apoptotic effects on activated NK cells. Our knowledge of the basic biology of IL-21 indicates that there are clinical situations, such as those in autoimmune disease, allergy and cancer, in which either ablation or augmentation of IL-21-mediated signalling might have therapeutic benefit. The interleukin-21 (IL-21)–IL-21-receptor system was discovered in 2000. It was immediately of great interest because of the homology of IL-21 to IL-2, IL-4 and IL-15, and of the IL-21-receptor subunit IL-21R to the β-subunit of the IL-2 receptor, and because the IL-21 receptor also contains the common cytokine-receptor γ-chain, the protein that is mutated in X-linked severe combined immunodeficiency. As we discuss, IL-21 has pleiotropic actions, from augmenting the proliferation of T cells and driving the differentiation of B cells into memory cells and terminally differentiated plasma cells to augmenting the activity of natural killer cells. Moreover, it has antitumour activity and might have a role in the development of autoimmunity, so these findings have implications for the treatment of cancer and autoimmune diseases.

Expression of T1ST2, the IL-33R, by Th2 cells requires GATA3. Resting Th2 cells express little GATA3, which is increased by IL-33 and a STAT5 activator, in turn increasing T1ST2 from its low-level expression on resting Th2 cells. Th2 cells that have upregulated T1ST2 produce IL-13, but not IL-4, in response to IL-33 plus a STAT5 activator in an antigen-independent, NF-κB-dependent, cyclosporin A (CsA)-resistant manner. Similarly, Th17 cells produce IL-17A in response to IL-1β and a STAT3 activator and Th1 cells produce IFNγ in response to IL-18 and a STAT4 inducer. Thus, each effector Th cell produces cytokines without antigenic stimulation in response to an IL-1 family member and a specific STAT activator, implying an innate mechanism through which memory CD4 T cells are recruited by an induced cytokine environment.

T helper cells that produce interleukin 17 (IL-17; 'T H -17 cells') are a distinct subset of proinflammatory cells whose in vivo function requires IL-23 but whose in vitro differentiation requires only IL-6 and transforming growth factor-β (TGF-β). We demonstrate here that IL-6 induced expression of IL-21 that amplified an autocrine loop to induce more IL-21 and IL-23 receptor in naive CD4 + T cells. Both IL-21 and IL-23, along with TGF-β, induced IL-17 expression independently of IL-6. The effects of IL-6 and IL-21 depended on STAT3, a transcription factor required for the differentiation of T H -17 cells in vivo . IL-21 and IL-23 induced the orphan nuclear receptor RORγt, which in synergy with STAT3 promoted IL-17 expression. IL-6 therefore orchestrates a series of 'downstream' cytokine-dependent signaling pathways that, in concert with TGF-β, amplify RORγt-dependent differentiation of T H -17 cells.

Background Gene expression has long been known to be influenced by the relative proximity of DNA regulatory elements. Topologically associating domains (TADs) are self-interacting genomic regions involved in regulating gene expression by controlling the proximity of these elements. Prior studies of TADs and their biological roles have revealed correlations between TAD changes and cellular differentiation. Here, we used Hi-C and RNA-seq data to correlate TCR-induced changes in TAD structure and gene expression in human CD4 + T cells. Results We developed a pipeline, Differentially Expressed Gene Enrichment Finder (DEGEF), that identifies regions of differentially expressed gene enrichment. Using DEGEF, we found that TCR-regulated genes cluster non-uniformly across the genome and that these clusters preferentially localized in regions of TAD rearrangement. Interestingly, clusters of upregulated genes preferentially formed new Hi-C contacts compared to downregulated clusters, suggesting that TCR-activated CD4 + T cells may regulate genes by changing stimulatory contacts rather than inhibitory contacts. Conclusions Our observations support a significant relationship between TAD rearrangements and changes in local gene expression. These findings indicate potentially important roles for TAD rearrangements in shaping their local regulatory environments and thus driving differential expression of nearby genes during CD4 + T cell activation. Moreover, they provide new insights into global mechanisms that regulate gene expression.