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Pollution from microplastics and anthropogenic fibres threatens lakes, but we know little about what factors predict its accumulation. Lakes may be especially contaminated because of long water retention times and proximity to pollution sources. Here, we surveyed anthropogenic microparticles, i.e., microplastics and anthropogenic fibres, in surface waters of 67 European lakes spanning 30° of latitude and large environmental gradients. By collating data from >2,100 published net tows, we found that microparticle concentrations in our field survey were higher than previously reported in lakes and comparable to rivers and oceans. We then related microparticle concentrations in our field survey to surrounding land use, water chemistry, and plastic emissions to sites estimated from local hydrology, population density, and waste production. Microparticle concentrations in European lakes quadrupled as both estimated mismanaged waste inputs and wastewater treatment loads increased in catchments. Concentrations decreased by 2 and 5 times over the range of surrounding forest cover and potential in-lake biodegradation, respectively. As anthropogenic debris continues to pollute the environment, our data will help contextualise future work, and our models can inform control and remediation efforts.

Aims: To update the benchmark from the 2006 National Survey, comparing users of NHS psychiatric intensive care (PICU) and low secure (LSU) services, and to define 'locked rehabilitation' (LRU) patient characteristics. Method: A cross-sectional census day questionnaire (November 2016) with a six month follow-up ending in May 2017. Results: 104 NHS units responded: 73 PICU, 644 patients; 17 LSU, 190 patients; 14 LRU, 183 patients. The typical PICU patient is younger, employed, stays for shorter periods, is more likely to suffer delayed discharge and mood disorder, have complex needs, have had mental health admissions in the last 12 months, be on 1:1 or higher observations, and have fewer antipsychotic and physical health medications but more benzodiazepines. The typical LSU patient is an out of area transfer, least likely to have been admitted for self-harm or non-concordance, and is of Black Other ethnic origin. The typical LRU patient is less likely to be married or have a long-term partner, has the lowest complex needs, but is most likely to have had physical examination and investigations. Discussion: There has been a rise in PICU and LSU patients from the Black and Minority Ethnic (BAME) population. Length of stay (LoS) for PICU and LSU patients has doubled; there are lower rates of delayed transfers of care. Conclusions : Our findings demonstrate that PICU and LSU services are providing care to the right patients as they were conceptualised in national guidance, and provide a benchmark for LRU patients.

Therapeutic targeting of immune checkpoints has garnered significant attention in the area of cancer immunotherapy, in which efforts have focused in particular on cytotoxic T lymphocyte antigen 4 (CTLA4) and PD1, both of which are members of the CD28 family. In autoimmunity, these same pathways can be targeted to opposite effect: to curb the over-exuberant immune response. The CTLA4 checkpoint serves as an exemplar, whereby CTLA4 activity is blocked by antibodies in cancer immunotherapy and augmented by the provision of soluble CTLA4 in autoimmunity. Here, we review the targeting of co-stimulatory molecules in autoimmune diseases, focusing in particular on agents directed at members of the CD28 or tumour necrosis factor receptor families. We present the state of the art in co-stimulatory blockade approaches, including rational combinations of immune inhibitory agents, and discuss the future opportunities and challenges in this field.Immune activating antibodies that target co-stimulatory molecules have altered the cancer therapy landscape. Here, Walker and colleagues discuss therapies — particularly those that target molecules in the same families as CTLA4 and PD1 or TNF receptor — that inhibit the immune system and are being investigated for the treatment of autoimmune diseases. They describe the future opportunities and challenges for the field, including combination approaches.

Cytotoxic T lymphocyte antigen 4 (CTLA-4) is an essential negative regulator of T cell immune responses whose mechanism of action is the subject of debate. CTLA-4 shares two ligands (CD80 and CD86) with a stimulatory receptor, CD28. Here, we show that CTLA-4 can capture its ligands from opposing cells by a process of trans-endocytosis. After removal, these costimulatory ligands are degraded inside CTLA-4—expressing cells, resulting in impaired costimulation via CD28. Acquisition of CD86 from antigen-presenting cells is stimulated by T cell receptor engagement and observed in vitro and in vivo. These data reveal a mechanism of immune regulation in which CTLA-4 acts as an effector molecule to inhibit CD28 costimulation by the cell-extrinsic depletion of ligands, accounting for many of the known features of the CD28—CTLA-4 system.

Key Points Cytotoxic T lymphocyte antigen 4 (CTLA4) and its homologue CD28 are crucial T cell proteins associated with immune regulation. They share the same ligands, CD80 and CD86, which are present on antigen-presenting cells (APCs). CTLA4-deficient mice suffer from fatal lymphoproliferative disease and die by 3–4 weeks of age, indicating that CTLA4 is an essential negative regulator of T cell responses. By contrast, CD28-deficient mice are immunocompromised. CTLA4 is a highly endocytic receptor that undergoes both recycling to the plasma membrane and degradation in lysosomes. The cytoplasmic domain, which is required for these functions, is highly conserved in mammals. CTLA4 is expressed by regulatory T (T Reg ) cells and activated conventional T cells. Evidence suggests that CTLA4 is important for T Reg cell suppressive function in many settings. The molecular mechanism of CTLA4 function is still undecided and a number of cell-intrinsic and cell-extrinsic mechanisms have been proposed. In vivo studies using bone marrow chimeric mice indicate that CTLA4-deficient T cells are not dysregulated in the presence of wild-type T cells. This suggests that the main non-redundant function of CTLA4 in vivo is a cell-extrinsic one. Emerging evidence suggests that one cell-extrinsic function of CTLA4 may be to downregulate CD80 and CD86 expression on APCs, thereby limiting the ability of APCs to stimulate T cells via CD28. Cytotoxic T lymphocyte antigen 4 (CTLA4) has long been known to have an important regulatory role in the immune system; however, its mechanisms of action have been the subject of considerable debate. This article reviews the strengths and limitations of the cell-intrinsic and cell-extrinsic models that have been proposed to explain the function of CTLA4. The T cell protein cytotoxic T lymphocyte antigen 4 (CTLA4) was identified as a crucial negative regulator of the immune system over 15 years ago, but its mechanisms of action are still under debate. It has long been suggested that CTLA4 transmits an inhibitory signal to the cells that express it. However, not all the available data fit with a cell-intrinsic function for CTLA4, and other studies have suggested that CTLA4 functions in a T cell-extrinsic manner. Here, we discuss the data for and against the T cell-intrinsic and -extrinsic functions of CTLA4.

CD28 and CTLA-4 (CD152) play essential roles in regulating T cell immunity, balancing the activation and inhibition of T cell responses, respectively. Although both receptors share the same ligands, CD80 and CD86, the specific requirement for two distinct ligands remains obscure. In the present study, we demonstrate that, although CTLA-4 targets both CD80 and CD86 for destruction via transendocytosis, this process results in separate fates for CTLA-4 itself. In the presence of CD80, CTLA-4 remained ligand bound, and was ubiquitylated and trafficked via late endosomes and lysosomes. In contrast, in the presence of CD86, CTLA-4 detached in a pH-dependent manner and recycled back to the cell surface to permit further transendocytosis. Furthermore, we identified clinically relevant mutations that cause autoimmune disease, which selectively disrupted CD86 transendocytosis, by affecting either CTLA-4 recycling or CD86 binding. These observations provide a rationale for two distinct ligands and show that defects in CTLA-4-mediated transendocytosis of CD86 are associated with autoimmunity.The inhibitory receptor CTLA-4 recognizes two ligands on opposing antigen-presenting cells, CD80 and CD86. Sansom and colleagues show CTLA-4 captures ligands by transendocytosis, whereupon low-affinity CD86 releases CTLA-4 at low pH to promote CTLA-4 recycling; however, high-affinity CD80 remains bound and targets CTLA-4 for ubiquitination and destruction.

Following the seminal discovery of insulin a century ago, treatment of individuals with type 1 diabetes (T1D) has been largely restricted to efforts to monitor and treat metabolic glucose dysregulation. The recent regulatory approval of the first immunotherapy that targets T cells as a means to delay the autoimmune destruction of pancreatic β-cells highlights the critical role of the immune system in disease pathogenesis and tends to pave the way for other immune-targeted interventions for T1D. Improving the efficacy of such interventions across the natural history of the disease will probably require a more detailed understanding of the immunobiology of T1D, as well as technologies to monitor residual β-cell mass and function. Here we provide an overview of the immune mechanisms that underpin the pathogenesis of T1D, with a particular emphasis on T cells.The first immune-targeted drug for type 1 diabetes (T1D), teplizumab, received regulatory approval by the US FDA in 2022. In this Review, Herold, Walker and colleagues examine the immune mechanisms that underpin T1D and provide an overview of immune-targeted strategies for T1D that are currently in development.

Significance The inhibitory protein cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is recognized as a crucial regulator of autoimmunity, but its precise mechanism of action is not yet fully understood. CTLA-4 can down-regulate expression of the costimulatory ligands CD80 and CD86 on antigen presenting cells, thereby reducing T-cell CD28 engagement. Here we demonstrate that quantitative changes in the level of CD28 engagement have functional consequences for T-cell differentiation toward follicular helper T cells (T FHs). These findings link CTLA-4 control of T-cell responses with the generation of high-affinity class-switched antibody responses. This generates an advanced conceptual framework for understanding the linked nature of CTLA-4 and CD28 functions and the role of this pathway in influencing autoimmunity. Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is an essential regulator of T-cell responses, and its absence precipitates lethal T-cell hyperactivity. However, whether CTLA-4 acts simply to veto the activation of certain clones or plays a more nuanced role in shaping the quality of T-cell responses is not clear. Here we report that T cells in CTLA-4–deficient mice show spontaneous T-follicular helper (T FH) differentiation in vivo, and this is accompanied by the appearance of large germinal centers (GCs). Remarkably, short-term blockade with anti–CTLA-4 antibody in wild-type mice is sufficient to elicit T FH generation and GC development. The latter occurs in a CD28-dependent manner, consistent with the known role of CTLA-4 in regulating the CD28 pathway. CTLA-4 can act by down-regulating CD80 and CD86 on antigen presenting cells (APCs), thereby altering the level of CD28 engagement. To mimic reduced CD28 ligation, we used mice heterozygous for CD28, revealing that the magnitude of CD28 engagement is tightly linked to the propensity for T FH differentiation. In contrast, other parameters of T-cell activation, including CD62L down-regulation and Ki67 expression, were relatively insensitive to altered CD28 level. Altered T FH generation as a result of graded reduction in CD28 was associated with decreased numbers of GC B cells and a reduction in overall GC size. These data support a model in which CTLA-4 control of immunity goes beyond vetoing T-cell priming and encompasses the regulation of T FH differentiation by graded control of CD28 engagement.

Follicular helper T (T FH ) cells are implicated in type 1 diabetes (T1D), and their development has been linked to CD28 costimulation. We tested whether T FH cells were decreased by costimulation blockade using the CTLA-4–immunoglobulin (Ig) fusion protein (abatacept) in a mouse model of diabetes and in individuals with new-onset T1D. Unbiased bioinformatics analysis identified that inducible costimulatory molecule (ICOS) + T FH cells and other ICOS + populations, including peripheral helper T cells, were highly sensitive to costimulation blockade. We used pretreatment T FH profiles to derive a model that could predict clinical response to abatacept in individuals with T1D. Using two independent approaches, we demonstrated that higher frequencies of ICOS + T FH cells at baseline were associated with a poor clinical response following abatacept administration. Therefore, T FH analysis may represent a new stratification tool, permitting the identification of individuals most likely to benefit from costimulation blockade. The CTLA-4–Ig fusion protein (abatacept) can have beneficial effects in autoimmune disease. Walker and colleagues show in mouse and human type 1 diabetes that abatacept targets pathogenic follicular helper T cells, and the frequencies of these cells at baseline can be used to stratify treatment responses in patients.