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The concepts of planetary boundaries are influential in the sustainability literature and assist in delineating the 'safe operating spaces' beyond which critical Earth system processes could collapse. Moving away from our current trajectory towards 'hothouse Earth' will require knowledge of how Earth systems have varied throughout the Holocene, and whether and how far we have deviated from past ranges of variability. Such information can inform decisions about where change could be resisted, accepted or where adaptation is inevitable. The need for information on long-term (Holocene) change provides an interface for palaeoecology and sustainability that remains underexploited. In this position paper, we explore this interface, first discussing the need for long-term perspectives and introducing examples where palaeoecology has been used in defining safe operating spaces and constraining limits of acceptable change. We describe advances in quantitative methods for analysis of time-series data that strengthen the contribution of palaeoecology to the concepts of planetary boundaries and safe operating spaces. We consider the importance of issues of scaling from landscape to regional and global scales in operationalising planetary boundaries concepts. We distil principles for this field of research going forward and introduce three case studies which will form the basis of research on these topics., (© 2025 The Author(s). Global Change Biology published by John Wiley & Sons Ltd.)

Population history-focused DNA and ancient DNA (aDNA) research in Africa has dramatically increased in the past decade, enabling increasingly fine-scale investigations into the continent's past. However, while international interest in human genomics research in Africa grows, major structural barriers limit the ability of African scholars to lead and engage in such research and impede local communities from partnering with researchers and benefitting from research outcomes. Because conversations about research on African people and their past are often held outside Africa and exclude African voices, an important step for African DNA and aDNA research is moving these conversations to the continent. In May 2023 we held the DNAirobi workshop in Nairobi, Kenya and here we synthesize what emerged most prominently in our discussions. We propose an ideal vision for population history-focused DNA and aDNA research in Africa in ten years' time and acknowledge that to realize this future, we need to chart a path connecting a series of "landmarks" that represent points of consensus in our discussions. These include effective communication across multiple audiences, reframed relationships and capacity building, and action toward structural changes that support science and beyond. We concluded there is no single path to creating an equitable and self-sustaining research ecosystem, but rather many possible routes linking these landmarks. Here we share our diverse perspectives as geneticists, anthropologists, archaeologists, museum curators, and educators to articulate challenges and opportunities for African DNA and aDNA research and share an initial map toward a more inclusive and equitable future., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To identify factors influencing implementation of machine learning algorithms (MLAs) that predict clinical deterioration in hospitalized adult patients and relate these to a validated implementation framework., Materials and Methods: A systematic review of studies of implemented or trialed real-time clinical deterioration prediction MLAs was undertaken, which identified: how MLA implementation was measured; impact of MLAs on clinical processes and patient outcomes; and barriers, enablers and uncertainties within the implementation process. Review findings were then mapped to the SALIENT end-to-end implementation framework to identify the implementation stages at which these factors applied., Results: Thirty-seven articles relating to 14 groups of MLAs were identified, each trialing or implementing a bespoke algorithm. One hundred and seven distinct implementation evaluation metrics were identified. Four groups reported decreased hospital mortality, 1 significantly. We identified 24 barriers, 40 enablers, and 14 uncertainties and mapped these to the 5 stages of the SALIENT implementation framework., Discussion: Algorithm performance across implementation stages decreased between in silico and trial stages. Silent plus pilot trial inclusion was associated with decreased mortality, as was the use of logistic regression algorithms that used less than 39 variables. Mitigation of alert fatigue via alert suppression and threshold configuration was commonly employed across groups., Conclusions: : There is evidence that real-world implementation of clinical deterioration prediction MLAs may improve clinical outcomes. Various factors identified as influencing success or failure of implementation can be mapped to different stages of implementation, thereby providing useful and practical guidance for implementers., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Objective: To derive a comprehensive implementation framework for clinical AI models within hospitals informed by existing AI frameworks and integrated with reporting standards for clinical AI research., Materials and Methods: (1) Derive a provisional implementation framework based on the taxonomy of Stead et al and integrated with current reporting standards for AI research: TRIPOD, DECIDE-AI, CONSORT-AI. (2) Undertake a scoping review of published clinical AI implementation frameworks and identify key themes and stages. (3) Perform a gap analysis and refine the framework by incorporating missing items., Results: The provisional AI implementation framework, called SALIENT, was mapped to 5 stages common to both the taxonomy and the reporting standards. A scoping review retrieved 20 studies and 247 themes, stages, and subelements were identified. A gap analysis identified 5 new cross-stage themes and 16 new tasks. The final framework comprised 5 stages, 7 elements, and 4 components, including the AI system, data pipeline, human-computer interface, and clinical workflow., Discussion: This pragmatic framework resolves gaps in existing stage- and theme-based clinical AI implementation guidance by comprehensively addressing the what (components), when (stages), and how (tasks) of AI implementation, as well as the who (organization) and why (policy domains). By integrating research reporting standards into SALIENT, the framework is grounded in rigorous evaluation methodologies. The framework requires validation as being applicable to real-world studies of deployed AI models., Conclusions: A novel end-to-end framework has been developed for implementing AI within hospital clinical practice that builds on previous AI implementation frameworks and research reporting standards., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Objective: To retrieve and appraise studies of deployed artificial intelligence (AI)-based sepsis prediction algorithms using systematic methods, identify implementation barriers, enablers, and key decisions and then map these to a novel end-to-end clinical AI implementation framework., Materials and Methods: Systematically review studies of clinically applied AI-based sepsis prediction algorithms in regard to methodological quality, deployment and evaluation methods, and outcomes. Identify contextual factors that influence implementation and map these factors to the SALIENT implementation framework., Results: The review identified 30 articles of algorithms applied in adult hospital settings, with 5 studies reporting significantly decreased mortality post-implementation. Eight groups of algorithms were identified, each sharing a common algorithm. We identified 14 barriers, 26 enablers, and 22 decision points which were able to be mapped to the 5 stages of the SALIENT implementation framework., Discussion: Empirical studies of deployed sepsis prediction algorithms demonstrate their potential for improving care and reducing mortality but reveal persisting gaps in existing implementation guidance. In the examined publications, key decision points reflecting real-word implementation experience could be mapped to the SALIENT framework and, as these decision points appear to be AI-task agnostic, this framework may also be applicable to non-sepsis algorithms. The mapping clarified where and when barriers, enablers, and key decisions arise within the end-to-end AI implementation process., Conclusions: A systematic review of real-world implementation studies of sepsis prediction algorithms was used to validate an end-to-end staged implementation framework that has the ability to account for key factors that warrant attention in ensuring successful deployment, and which extends on previous AI implementation frameworks., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

East African ecosystems have been shaped by long-term socio-ecological-environmental interactions. Although much previous work on human-environment interrelationships have emphasised the negative impacts of human interventions, a growing body of work shows that there have also often been strong beneficial connections between people and ecosystems, especially in savanna environments. However, limited information and understanding of past interactions between humans and ecosystems of periods longer than a century hampers effective management of contemporary environments. Here, we present a late Holocene study of pollen, fern spore, fungal spore, and charcoal analyses from radiocarbon-dated sediment sequences and assess this record against archaeological and historical data to describe socio-ecological changes on the Laikipia Plateau in Rift Valley Province, Kenya. The results suggest a landscape characterised by closed forests between 2268 years before present (cal year BP) and 1615 cal year BP when there was a significant change to a more open woodland/grassland mosaic that continues to prevail across the study area. Increased amounts of charcoal in the sediment are observed for this same period, becoming particularly common from around 900 cal year BP associated with fungal spores commonly linked to the presence of herbivores. It is likely these trends reflect changes in land use management as pastoral populations improved and extended pasture, using fire to eradicate disease-prone habitats. Implications for contemporary land use management are discussed in the light of these findings., (© 2021. The Author(s).)

Background: Acquired activated protein C resistance (APCr) has been identified in antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE)., Objective: To assess agreement between the ST-Genesia ® and CAT analysers in identifying APCr prevalence in APS/SLE patients, using three thrombin generation (TG) methods., Methods: APCr was assessed with the ST-Genesia using STG-ThromboScreen and with the CAT using recombinant human activated protein C and Protac ® in 105 APS, 53 SLE patients and 36 thrombotic controls. Agreement was expressed in % and by Cohen's kappa coefficient., Results: APCr values were consistently lower with the ST-Genesia ® compared to the CAT, using either method, in both APS and SLE patients. Agreement between the two analysers in identifying APS and SLE patients with APCr was poor (≤65.9%, ≤0.20) or fair (≤68.5%, ≥0.29), regardless of TG method, respectively; no agreement was observed in thrombotic controls. APCr with both the ST Genesia and the CAT using Protac ® , but not the CAT using rhAPC, was significantly greater in triple antiphospholipid antibody (aPL) APS patients compared to double/single aPL patients ( p < 0.04) and in thrombotic SLE patients compared to non-thrombotic SLE patients ( p < 0.05). Notably, the ST-Genesia ® , unlike the CAT, with either method, identified significantly greater APCr in pregnancy morbidity (median, confidence intervals; 36.9%, 21.9-49.0%) compared to thrombotic (45.7%, 39.6-55.5%) APS patients ( p = 0.03)., Conclusion: Despite the broadly similar methodology used by CAT and ST-Genesia ® , agreement in APCr was poor/fair, with results not being interchangeable. This may reflect differences in the TG method, use of different reagents, and analyser data handling.

Purpose: The complex and occasionally chaotic nature of health care has been previously described in the literature, as has the broadening recognition that different management approaches are required for different types of problems rather than a "one size fits all" approach. The CYNEFIN framework from Snowden outlines a consistent cognitive approach that offers the leader and leadership team an ability to urgently apply the correct actions to a given situation. This paper proposes a variant CYNEFIN approach for healthcare., Design/methodology/approach: Consistent and accurate decision-making within health care is the hallmark of an effective and pragmatic leader and leadership team. An awareness of how one's cognitive biases and heuristics may adversely impact on this cognitive process is paramount, as is an understanding of the calibration between fast and slow thinking., Findings: The authors propose a variant CYNEFIN approach for health care of "act-probe-sense-respond" to resolve complex and time-critical emergency scenarios, using the differing contexts of a cardiac arrest and an evolving crisis management problem as examples. The variant serves as a pragmatic sense-making framework for the health-care leader and leadership team that can be adopted for many time-critical crisis situations., Originality/value: The variant serves as a pragmatic sense-making framework for the health-care leader that can be adopted for many crisis situations., (© Paul James Lane, Robyn Clay-Williams, Andrew Johnson, Vidula Garde and Leah Barrett-Beck.)

Co-stimulation is a prerequisite for pathogenic activity in T cell-mediated diseases and has been demonstrated to achieve tolerance in organ-specific autoimmunity as a therapeutic target. Here, we evaluated the involvement of the tumor necrosis factor family members CD30 and OX40 in immune-complex mediated kidney disease. In vitro stimulation and proliferation studies were performed with CD4 + cells from wild type and CD30/OX40 double knock-out (CD30OX40 -/- ) mice. In vivo studies were performed by induction of nephrotoxic serum nephritis in wild type, CD30OX40 - /- , CD30 -/- , OX40 -/- , reconstituted Rag1 -/- and C57Bl/6J mice treated with αCD30L αOX40L antibodies. CD30, OX40 and their ligands were upregulated on various leukocytes in nephrotoxic serum nephritis. CD30OX40 -/- mice, but not CD30 -/- or OX40 -/- mice were protected from nephrotoxic serum nephritis. Similar protection was found in Rag1 -/- mice injected with CD4 + T cells from CD30OX40 -/- mice compared to Rag1 -/- mice injected with CD4 + T cells from wild type mice. Furthermore, CD4 + T cells deficient in CD30OX40 -/- displayed decreased expression of CCR6 in vivo. CD30OX40 -/- cells were fully capable of differentiating into disease mediating T helper cell subsets, but showed significantly decreased levels of proliferation in vivo and in vitro compared to wild type cells. Blocking antibodies against CD30L and OX40L ameliorated nephrotoxic serum nephritis without affecting pan-effector or memory T cell populations. Thus, our results indicate disease promotion via CD30 and OX40 signaling due to facilitation of exaggerated T cell proliferation and migration of T helper 17 cells in nephrotoxic serum nephritis. Hence, co-stimulation blockade targeting the CD30 and OX40 signaling pathways may provide a novel therapeutic strategy in autoimmune kidney disease., (Copyright © 2021 International Society of Nephrology. All rights reserved.)

Rapid rates of land use and land cover change (LULCC) in eastern Africa and limited instances of genuinely equal partnerships involving scientists, communities and decision makers challenge the development of robust pathways toward future environmental and socioeconomic sustainability. We use a participatory modelling tool, Kesho, to assess the biophysical, socioeconomic, cultural and governance factors that influenced past (1959-1999) and present (2000-2018) LULCC in northern Tanzania and to simulate four scenarios of land cover change to the year 2030. Simulations of the scenarios used spatial modelling to integrate stakeholders' perceptions of future environmental change with social and environmental data on recent trends in LULCC. From stakeholders' perspectives, between 1959 and 2018, LULCC was influenced by climate variability, availability of natural resources, agriculture expansion, urbanization, tourism growth and legislation governing land access and natural resource management. Among other socio-environmental-political LULCC drivers, the stakeholders envisioned that from 2018 to 2030 LULCC will largely be influenced by land health, natural and economic capital, and political will in implementing land use plans and policies. The projected scenarios suggest that by 2030 agricultural land will have expanded by 8-20% under different scenarios and herbaceous vegetation and forest land cover will be reduced by 2.5-5% and 10-19% respectively. Stakeholder discussions further identified desirable futures in 2030 as those with improved infrastructure, restored degraded landscapes, effective wildlife conservation, and better farming techniques. The undesirable futures in 2030 were those characterized by land degradation, poverty, and cultural loss. Insights from our work identify the implications of future LULCC scenarios on wildlife and cultural conservation and in meeting the Sustainable Development Goals (SDGs) and targets by 2030. The Kesho approach capitalizes on knowledge exchanges among diverse stakeholders, and in the process promotes social learning, provides a sense of ownership of outputs generated, democratizes scientific understanding, and improves the quality and relevance of the outputs., Competing Interests: The authors have declared that no competing interests exist.

Background: Variability remains a challenge in lupus anticoagulant (LA) testing., Objective: To validate LA test performance between Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking (APS ACTION) Core laboratories and examine agreement in LA status between Core and local/hospital laboratories contributing patients to this prospective registry., Methods: Five Core laboratories used the same reagents, analyzer type, protocols, and characterized samples for LA validation. Non-anticoagulated registry samples were retested at the corresponding regional Core laboratories and anticoagulated samples at a single Core laboratory. Categorical agreement and discrepancies in LA status between Core and local/hospital laboratories were analyzed., Results: Clotting times for the reference/characterized plasmas used for normalized ratios were similar between Core laboratories (CV <4%); precision and agreement for LA positive/negative plasma were similar (all CV ≤5%) in the four laboratories that completed both parts of the validation exercise; 418 registry samples underwent LA testing. Agreement for LA positive/negative status between Core and local/hospital laboratories was observed in 87% (115/132) non-anticoagulated and 77% (183/237) anticoagulated samples. However, 28.7% (120/418) of samples showed discordance between the Core and local/hospital laboratories or equivocal LA results. Some of the results of the local/hospital laboratories might have been unreliable in 24.7% (41/166) and 23% (58/252) of the total non-anticoagulated and anticoagulated samples, respectively. Equivocal results by the Core laboratory might have also contributed to discordance., Conclusions: Laboratories can achieve good agreement in LA performance by use of the same reagents, analyzer type, and protocols. The standardized Core laboratory results underpin accurate interpretation of APS ACTION clinical data., (© 2019 International Society on Thrombosis and Haemostasis.)

Background: Tissue factor pathway inhibitor (TFPI) antibodies, which have been reported in patients with antiphospholipid syndrome (APS), may impair TFPI activity and contribute to hypercoagulability, but their role in APS and in thrombosis remains undefined., Objective/methods: We assessed the presence and avidity of TFPI IgG antibodies, associations with protein C IgG antibodies and associations with clinical disease severity, in 50 patients with thrombotic APS and 50 thrombotic control patients, on long term anticoagulation with warfarin., Results: Thrombotic APS patients had a significantly higher prevalence of TFPI IgG antibodies (40%; 20/50) compared to thrombotic controls (18%; 9/50). TFPI antibodies were predominantly high avidity in APS (50%, 10/20 of positive patients) and strongly associated with a severe thrombotic phenotype (venous and arterial thromboembolism or recurrent thromboembolic episodes despite therapeutic anticoagulation) (odds ratio (OR): 12.0, 95%CI: 2.2-66.1, p = 0.004), while thrombotic control patients mainly showed low avidity antibodies (78%, 7/9 of positive patients). Coexistence of TFPI and protein C IgG antibodies, regardless of their avidity, was strongly associated with a more severe thrombotic phenotype in APS patients (OR: 20.2, 95%CI: 2.0-47.0, p < 0.0001) and also in thrombotic controls (OR: 75.0, 95%CI 1.2-195, p = 0.02)., Conclusions: Coexistent TFPI and protein C IgG antibodies, irrespective of their avidity, may be a useful marker for a severe thrombotic phenotype in thrombotic patients. This suggests a possibly pathophysiological relationship between the two antibodies, predisposing to thrombosis with a possibly more general role in the development of thrombotic complications., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Experienced T cells exhibit immunological memory via a rapid recall response, responding to restimulation much faster than naïve T cells. The formation of immunological memory starts during an initial slow response, when naïve T cells become transformed to proliferating T blast cells, and inducible immune response genes are reprogrammed as active chromatin domains. We demonstrated that these active domains are supported by thousands of priming elements which cooperate with inducible transcriptional enhancers to enable efficient responses to stimuli. At the conclusion of this response, a small proportion of these cells return to the quiescent state as long-term memory T cells. We proposed that priming elements can be established in a hit-and-run process dependent on the inducible factor AP-1, but then maintained by the constitutive factors RUNX1 and ETS-1. This priming mechanism may also function to render genes receptive to additional differentiation-inducing factors such as GATA3 and TBX21 that are encountered under polarizing conditions. The proliferation of recently activated T cells and the maintenance of immunological memory in quiescent memory T cells are also dependent on various cytokine signaling pathways upstream of AP-1. We suggest that immunological memory is established by T cell receptor signaling, but maintained by cytokine signaling.

This paper presents the results of a consensus-driven process identifying 50 priority research questions for historical ecology obtained through crowdsourcing, literature reviews, and in-person workshopping. A deliberative approach was designed to maximize discussion and debate with defined outcomes. Two in-person workshops (in Sweden and Canada) over the course of two years and online discussions were peer facilitated to define specific key questions for historical ecology from anthropological and archaeological perspectives. The aim of this research is to showcase the variety of questions that reflect the broad scope for historical-ecological research trajectories across scientific disciplines. Historical ecology encompasses research concerned with decadal, centennial, and millennial human-environmental interactions, and the consequences that those relationships have in the formation of contemporary landscapes. Six interrelated themes arose from our consensus-building workshop model: (1) climate and environmental change and variability; (2) multi-scalar, multi-disciplinary; (3) biodiversity and community ecology; (4) resource and environmental management and governance; (5) methods and applications; and (6) communication and policy. The 50 questions represented by these themes highlight meaningful trends in historical ecology that distill the field down to three explicit findings. First, historical ecology is fundamentally an applied research program. Second, this program seeks to understand long-term human-environment interactions with a focus on avoiding, mitigating, and reversing adverse ecological effects. Third, historical ecology is part of convergent trends toward transdisciplinary research science, which erodes scientific boundaries between the cultural and natural.

East African elephants have been hunted for their ivory for millennia but the nineteenth century witnessed strongly escalating demand from Europe and North America. It has been suggested that one consequence was that by the 1880s elephant herds along the coast had become scarce, and to meet demand, trade caravans trekked farther into interior regions of East Africa, extending the extraction frontier. The steady decimation of elephant populations coupled with the extension of trade networks have also been claimed to have triggered significant ecological and socio-economic changes that left lasting legacies across the region. To explore the feasibility of using an isotopic approach to uncover a 'moving frontier' of elephant extraction, we constructed a baseline isotope data set (δ13C, δ15N, δ18O and 87Sr/86Sr) for historic East African elephants known to have come from three distinct regions (coastal, Rift Valley, and inland Lakes). Using the isotope results with other climate data and geographical mapping tools, it was possible to characterise elephants from different habitats across the region. This baseline data set was then used to provenance elephant ivory of unknown geographical provenance that was exported from East Africa during the late nineteenth and early twentieth centuries to determine its likely origin. This produced a better understanding of historic elephant geography in the region, and the data have the potential to be used to provenance older archaeological ivories, and to inform contemporary elephant conservation strategies., Competing Interests: The authors have declared that no competing interests exist.

The tumour necrosis factor receptor OX40 (CD134) is activated by its cognate ligand OX40L (CD134L, CD252) and functions as a T cell co-stimulatory molecule. OX40-OX40L interactions have been proposed as a potential therapeutic target for treating autoimmunity. OX40 is expressed on activated T cells, and in the mouse at rest on regulatory T cells (Treg). OX40L is found on antigen-presenting cells, activated T cells and others including lymphoid tissue inducer cells, some endothelia and mast cells. Expression of both molecules is increased after antigen presentation occurs and also in response to multiple other pro-inflammatory factors including CD28 ligation, CD40L ligation and interferon-gamma signaling. Their interactions promote T cell survival, promote an effector T cell phenotype, promote T cell memory, tend to reduce regulatory function, increase effector cytokine production and enhance cell mobility. In some circumstances, OX40 agonism may be associated with increased tolerance, although timing with respect to antigenic stimulus is important. Further, recent work has suggested that OX40L blockade may be more effective than OX40 blockade in reducing autoimmunity. This article reviews the expression of OX40 and OX40L in health, the effects of their interactions and insights from their under- or over-expression. We then review OX40 and OX40L expression in human autoimmune disease, identified associations of variations in their genes (TNFRSF4 and TNFSF4, respectively) with autoimmunity, and data from animal models of human diseases. A rationale for blocking OX40-OX40L interaction in human autoimmunity is then presented along with commentary on the one trial of OX40L blockade in human disease conducted to date. Finally, we discuss potential problems with clinical use of OX40-OX40L directed pharmacotherapy.

Monitoring warfarin anticoagulation in patients with thrombotic antiphospholipid syndrome (APS) may be complicated by the sensitivity of different thromboplastins to lupus anticoagulant. The aim of this study was to compare the degree of anticoagulation intensity in thrombotic APS and non-APS patients (50 in each group) on long-term warfarin, by measurement of the INR with two widely available thromboplastins with instrument-specific ISI values, and to investigate the potential role of amidolytic FX levels and thrombin generation (TG) testing in the assessment of anticoagulant intensity in thrombotic APS patients. There were no overall differences in INR between reagents or patient groups, but 20% (10/50) of APS patients showed ≥0.5 INR unit difference between reagents, which would have resulted in altered clinical management in some patients. FX levels were useful in assessing anticoagulation intensity for INR 2.0-3.0, but showed poor utility at INR ≥3.5 where the lowest measured FX level was 12IU/dL. In contrast, ETP and peak thrombin showed significant inverse correlations with the INR, suggesting that TG testing may be helpful in the determination of true anticoagulant intensity in APS patients, including those with ≥3.5 INR. TG testing also highlighted a subgroup of APS patients with increased peak thrombin relative to the intensity of anticoagulation as assessed by INR and FX, suggesting that TG testing may be useful in identifying an ongoing prothrombotic state in patients with apparently adequate anticoagulation intensity as assessed by INR., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

αβT cell development depends upon serial migration of thymocyte precursors through cortical and medullary microenvironments, enabling specialized stromal cells to provide important signals at specific stages of their development. Although conventional αβT cells are subject to clonal deletion in the medulla, entry into the thymus medulla also fosters αβT cell differentiation. For example, during postnatal periods, the medulla is involved in the intrathymic generation of multiple αβT cell lineages, notably the induction of Foxp3(+) regulatory T cell development and the completion of invariant NKT cell development. Although migration of conventional αβT cells to the medulla is mediated by the chemokine receptor CCR7, how other T cell subsets gain access to medullary areas during their normal development is not clear. In this study, we show that combining a panel of thymocyte maturation markers with cell surface analysis of CCR7 and CCR4 identifies distinct stages in the development of multiple αβT cell lineages in the thymus. Although Aire regulates expression of the CCR4 ligands CCL17 and CCL22, we show that CCR4 is dispensable for thymocyte migration and development in the adult thymus, demonstrating defective T cell development in Aire(-/-) mice is not because of a loss of CCR4-mediated migration. Moreover, we reveal that CCR7 controls the development of invariant NKT cells by enabling their access to IL-15 trans-presentation in the thymic medulla and influences the balance of early and late intrathymic stages of Foxp3(+) regulatory T cell development. Collectively, our data identify novel roles for CCR7 during intrathymic T cell development, highlighting its importance in enabling multiple αβT cell lineages to access the thymic medulla., (Copyright © 2014 The Authors.)

Introduction: The investigation of platelet function by aggregometry requires specialist equipment and is labour intensive. We have developed an automated platelet aggregation method on a routine coagulation analyser., Methods: We used a CS-2000i (Sysmex) with prototype software to perform aggregation in platelet-rich plasma (PRP), using the following agonists: ADP (0.5-10 μm), epinephrine (0.5-10 μm), collagen (0.5-10 mg/μL), ristocetin (0.75-1.25 mg/mL) and arachidonic acid (0.12-1.0 mm). Platelet agonists were from Hyphen Biomed, and an AggRAM aggregometer (Helena Biosciences) was used as the reference instrument., Results: CS-2000i reaction cuvette stirrer speed was found to influence reaction sensitivity and was optimized to 800 rpm. There were no clinically significant changes in aggregation response when the PRP platelet count was 150-480 x 10(9) /L, but below this there were changes in the maximum amplitude (MA) and slope (rate). Dose response with each of the agonists was comparable between CS-2000i and an AggRAM aggregometer and normal subjects receiving antiplatelet drugs. Aggregation imprecision was similar on both the CS-2000i and AggRAM systems, with a cv for 2-5 μm ADP MA and slope varying between 3-12%., Conclusion: Our preliminary studies indicated that optimal sensitivity using the CS-2000i was obtained with a reaction cuvette stirrer speed of 800 rpm and a PRP platelet count of 200-300 x 10(9) /L; aggregation with a PRP count <100 x 10(9) /L showed poor sensitivity. Imprecision and detection of antiplatelet drug effects was similar between the CS-2000i and AggRAM. These data demonstrate that CS-2000i is comparable to a stand-alone aggregometer, although CS-2000i has the advantages of walk-away technology and also required a smaller sample volume than the AggRAM (44% less)., (© 2013 John Wiley & Sons Ltd.)

Although current thinking has focused on genetic variation between individuals and environmental influences as underpinning susceptibility to both autoimmunity and cancer, an alternative view is that human susceptibility to these diseases is a consequence of the way the immune system evolved. It is important to remember that the immunological genes that we inherit and the systems that they control were shaped by the drive for reproductive success rather than for individual survival. It is our view that human susceptibility to autoimmunity and cancer is the evolutionarily acceptable side effect of the immune adaptations that evolved in early placental mammals to accommodate a fundamental change in reproductive strategy. Studies of immune function in mammals show that high affinity antibodies and CD4 memory, along with its regulation, co-evolved with placentation. By dissection of the immunologically active genes and proteins that evolved to regulate this step change in the mammalian immune system, clues have emerged that may reveal ways of de-tuning both effector and regulatory arms of the immune system to abrogate autoimmune responses whilst preserving protection against infection. Paradoxically, it appears that such a detuned and deregulated immune system is much better equipped to mount anti-tumor immune responses against cancers.

The current study explored the relationship between lymphoid tissue inducer (LTi) cells and patients' clinical and immunological status. LTi cells are critical for lymphoid tissue development and maintenance of CD4 T cell-dependent immune responses. The percentage of CD117+CD3-CD56-CD127+ RORγ+ LTi cells isolated from human tonsils was determined and correlated with changes in other immune subsets and clinical factors. We found that the portion of LTi and CD4 T cells was significantly increased in chronic tonsillitis compared to non-inflamed tonsils. Additionally, the expression of OX40 by memory CD4 T cells and OX40 ligand (OX40L) and interleukin (IL)-22 by LTi cells was higher in chronically inflamed tonsils. The treatment for tonsillitis with ibuprofen did not alter LTi cell viability and the expression of OX40L and IL-22. These results demonstrate that during chronic inflammation, LTi cells are increased and express higher levels of OX40L and IL-22, and this is correlated with an increase in memory CD4 T cells.

The development of CD4(+) helper and CD8(+) cytotoxic T-cells expressing the αβ form of the T-cell receptor (αβTCR) takes place in the thymus, a primary lymphoid organ containing distinct cortical and medullary microenvironments. While the cortex represents a site of early T-cell precursor development, and the positive selection of CD4(+)8(+) thymocytes, the thymic medulla plays a key role in tolerance induction, ensuring that thymic emigrants are purged of autoreactive αβTCR specificities. In recent years, advances have been made in understanding the development and function of thymic medullary epithelial cells, most notably the subset defined by expression of the Autoimmune Regulator (Aire) gene. Here, we summarize current knowledge of the developmental mechanisms regulating thymus medulla development, and examine the role of the thymus medulla in recessive (negative selection) and dominant (T-regulatory cell) tolerance.

Thymocytes expressing the invariant Vγ5 γδT-cell receptor represent progenitors of dendritic epidermal T-cells (DETC) that play an important immune surveillance role in the skin. In contrast to the bulk of αβT-cell development, Vγ5(+) DETC progenitor development occurs exclusively in fetal thymus. Whilst αβT-cell development is known to require chemokine receptor mediated migration through distinct thymus regions, culminating in medullary entry and thymic egress, the importance and control of intrathymic migration for DETC progenitors is unclear. We recently revealed a link between Vγ5(+) DETC progenitor development and medullary thymic epithelial cells expressing Aire, a known regulator of thymic chemokine expression, demonstrating that normal Vγ5(+) DETC progenitor development requires regulated intramedullary positioning. Here we investigate the role of chemokines and their receptors during intrathymic Vγ5(+) DETC progenitor development and establishment of the DETC pool in the skin. We report that thymic medullary accumulation of Vγ5(+) DETC progenitors is a G-protein coupled receptor dependent process. However, this process occurs independently of Aire's influences on intrathymic chemokines, and in the absence of CCR4 and CCR7 expression by DETC progenitors. In contrast, analysis of epidermal γδT-cells at neonatal and adult stages in CCR4(-/-) mice reveals that reduced numbers of DETC in adult epidermis are not a consequence of diminished intrathymic embryonic development, nor deficiencies in initial epidermal seeding in the neonate. Collectively, our data reveal differences in the chemokine receptor requirements for intrathymic migration of αβ and invariant γδT-cells, and highlight a differential role for CCR4 in the maintenance, but not initial seeding, of DETC in the epidermis.

A key role of the thymic medulla is to negatively select autoreactive CD4(+) and CD8(+) thymocytes, a process important for T cell tolerance induction. However, the involvement of the thymic medulla in other aspects of αβ T cell development, including the generation of Foxp3(+) natural regulatory T cells (nTreg cells) and the continued maturation of positively selected conventional αβ T cells, is unclear. We show that newly generated conventional CD69(+)Qa2(-) CD4 single-positive thymocytes mature to the late CD69(-)Qa2(+) stage in the absence of RelB-dependent medullary thymic epithelial cells (mTECs). Furthermore, an increasing ability to continue maturation extrathymically is observed within the CD69(+)CCR7(-/lo)CCR9(+) subset of conventional SP4 thymocytes, providing evidence for an independence from medullary support by the earliest stages after positive selection. In contrast, Foxp3(+) nTreg cell development is medullary dependent, with mTECs fostering the generation of Foxp3(-)CD25(+) nTreg cell precursors at the CD69(+)CCR7(+)CCR9(-) stage. Our results demonstrate a differential requirement for the thymic medulla in relation to CD4 conventional and Foxp3(+) thymocyte lineages, in which an intact mTEC compartment is a prerequisite for Foxp3(+) nTreg cell development through the generation of Foxp3(-)CD25(+) nTreg cell precursors.

In the adult thymus, the development of self-tolerant thymocytes requires interactions with thymic epithelial cells (TECs). Although both cortical and medullary TECs (cTECs/mTECs) are known to arise from common bipotent TEC progenitors, the phenotype of these progenitors and the timing of the emergence of these distinct lineages remain unclear. Here, we have investigated the phenotype and developmental properties of bipotent TEC progenitors during cTEC/mTEC lineage development. We show that TEC progenitors can undergo a stepwise acquisition of first cTEC and then mTEC hallmarks, resulting in the emergence of a progenitor population simultaneously expressing the cTEC marker CD205 and the mTEC regulator Receptor Activator of NF-κB (RANK). In vivo analysis reveals the capacity of CD205(+) TECs to generate functionally competent cortical and medullary microenvironments containing both cTECs and Aire(+) mTECs. Thus, TEC development involves a stage in which bipotent progenitors can co-express hallmarks of the cTEC and mTEC lineages through sequential acquisition, arguing against a simple binary model in which both lineages diverge simultaneously from bipotent lineage negative TEC progenitors. Rather, our data reveal an unexpected overlap in the phenotypic properties of these bipotent TECs with their lineage-restricted counterparts., (© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

T cell tolerance in the thymus is a key step in shaping the developing T cell repertoire. Thymic medullary epithelial cells play multiple roles in this process, including negative selection of autoreactive thymocytes, influencing thymic dendritic cell positioning, and the generation of Foxp3(+) regulatory T cells. Previous studies show that medullary thymic epithelial cell (mTEC) development involves hemopoietic cross-talk, and numerous TNFR superfamily members have been implicated in this process. Whereas CD40 and RANK represent key examples, interplay between these receptors, and the individual cell types providing their ligands at both fetal and adult stages of thymus development, remain unclear. In this study, by analysis of the cellular sources of receptor activator for NF-κB ligand (RANKL) and CD40L during fetal and adult cross-talk in the mouse, we show that the innate immune cell system drives initial fetal mTEC development via expression of RANKL, but not CD40L. In contrast, cross-talk involving the adaptive immune system involves both RANKL and CD40L, with analysis of distinct subsets of intrathymic CD4(+) T cells revealing a differential contribution of CD40L by conventional, but not Foxp3(+) regulatory, T cells. We also provide evidence for a stepwise involvement of TNFRs in mTEC development, with CD40 upregulation induced by initial RANK signaling subsequently controlling proliferation within the mTEC compartment. Collectively, our findings show how multiple hemopoietic cell types regulate mTEC development through differential provision of RANKL/CD40L during ontogeny, revealing molecular differences in fetal and adult hemopoietic cross-talk. They also suggest a stepwise process of mTEC development, in which RANK is a master player in controlling the availability of other TNFR family members.

Phylogeny shows that CD4 T cell memory and lymph nodes coevolved in placental mammals. In ontogeny, retinoic acid orphan receptor (ROR)γ-dependent lymphoid tissue inducer (LTi) cells program the development of mammalian lymph nodes. In this study, we show that although primary CD4 T cell expansion is normal in RORγ-deficient mice, the persistence of memory CD4 T cells is RORγ-dependent. Furthermore, using bone marrow chimeric mice we demonstrate that LTi cells are the key RORγ-expressing cell type sufficient for memory CD4 T cell survival in the absence of persistent Ag. This effect was specific for CD4 T cells, as memory CD8 T cells survived equally well in the presence or absence of LTi cells. These data demonstrate a novel role for LTi cells, archetypal members of the innate lymphoid cell family, in supporting memory CD4 T cell survival in vivo.

The thymic medulla provides a specialized microenvironment for the negative selection of T cells, with the presence of autoimmune regulator (Aire)-expressing medullary thymic epithelial cells (mTECs) during the embryonic-neonatal period being both necessary and sufficient to establish long-lasting tolerance. Here we showed that emergence of the first cohorts of Aire(+) mTECs at this key developmental stage, prior to αβ T cell repertoire selection, was jointly directed by Rankl(+) lymphoid tissue inducer cells and invariant Vγ5(+) dendritic epidermal T cell (DETC) progenitors that are the first thymocytes to express the products of gene rearrangement. In turn, generation of Aire(+) mTECs then fostered Skint-1-dependent, but Aire-independent, DETC progenitor maturation and the emergence of an invariant DETC repertoire. Hence, our data attributed a functional importance to the temporal development of Vγ5(+) γδ T cells during thymus medulla formation for αβ T cell tolerance induction and demonstrated a Rank-mediated reciprocal link between DETC and Aire(+) mTEC maturation., (Copyright © 2012 Elsevier Inc. All rights reserved.)

PHYLOGENY SUGGESTS THAT THE EVOLUTION OF PLACENTATION IN MAMMALS WAS ACCOMPANIED BY SUBSTANTIAL CHANGES IN THE MAMMALIAN IMMUNE SYSTEM: in particular lymph nodes and CD4 high affinity memory antibody responses co-evolved during the same period. Lymphoid tissue inducer cells (LTi) are members of an emerging family of innate lymphoid cells (ILCs) that are crucial for lymph node development, but our studies have indicated that they also play a pivotal role in the long-term maintenance of memory CD4 T cells in adult mammals through their expression of the tumor necrosis family members, OX40- and CD30-ligands. Additionally, our studies have shown that these two molecules are also key operators in CD4 effector function, as their absence obviates the need for the FoxP3 dependent regulatory T (T(regs)) cells that prevent CD4 driven autoimmune responses. In this perspective article, we summarize findings from our group over the last 10 years, and focus specifically on the role of LTi in thymus. We suggest that like memory CD4 T cells, LTi also play a role in the selection and maintenance of the T(regs) that under normal circumstances are absolutely required to regulate CD4 effector cells.

Lymphoid tissue inducer cells (LTi) are a relatively new arrival on the immunological cellular landscape, having first been characterized properly only 15 years ago. They are members of an emerging family of innate lymphoid cells (ILCs). Elucidation of their function reveals links not only with the ancient innate immune system, but also with adaptive immune responses, in particular the development of lymph nodes and CD4(+) T cell memory immune responses, which on one hand underpin the success of vaccination strategies, and on the other hand drive many human immunologically mediated diseases. This perspective article is not an exhaustive account of the role of LTi in the development of lymphoid tissues, as there have been many excellent reviews published already. Instead, we combine current knowledge of genetic phylogeny and comparative immunology, together with classical mouse genetics, to suggest how LTi might have evolved from a primitive lymphocytic innate cell in the ancestral 500-million-year-old vertebrate immune system into a cell critical for adaptive CD4(+) T cell immune responses in mammals., (© 2012 New York Academy of Sciences.)

CD4(+) effector and memory T cells play a pivotal role in the development of both normal and pathogenic immune responses. This review focuses on the molecular and cellular mechanisms that regulate their development, with particular focus on the tumor necrosis factor superfamily members OX40 (TNFRSF4) and CD30 (TNFRSF8). We discuss the evidence that in mice, these molecular signaling pathways act synergistically to regulate the development of both effector and memory CD4(+) T cells but that the cells that regulate memory versus effector function are distinct, effectively allowing the independent regulation of the memory and effector CD4(+) T-cell pools., (© 2011 John Wiley & Sons A/S.)

Our previous studies have implicated signaling through the tumor necrosis family receptors OX40 and CD30 as critical for maintaining CD4 memory responses. We show that signals through both molecules are also required for CD4 effector-mediated autoimmune tissue damage. Under normal circumstances, male mice deficient in the forkhead transcription factor FoxP3, which lack regulatory CD4 T cells, develop lethal autoimmune disease in the first few weeks of life. However, in the combined absence of OX40 and CD30, FoxP3-deficient mice develop normally and breed successfully. The extensive tissue infiltration and organ destruction characteristic of FoxP3 disease does not appear in these mice, and their mortality is not associated with autoimmunity. Although the absence of OX40 plays the dominant role, FoxP3-deficient mice sufficient in CD30 but deficient in OX40 signals still eventually develop lethal disease. This result was supported by the observation that blocking antibodies to OX40 and CD30 ligands also abrogated disease mediated by FoxP3-deficient T cells. These observations identify OX40 and CD30 signals as essential for the development of clinically relevant CD4-dependent autoimmunity and suggest that combination therapies that abrogate these signals might be used to treat established human autoimmune diseases.

The entry of T cell progenitors to the thymus marks the beginning of a multistage developmental process that culminates in the generation of self-MHC-restricted CD4(+) and CD8(+) T cells. Although multiple factors including the chemokine receptors CCR7 and CCR9 are now defined as important mediators of progenitor recruitment and colonization in both the fetal and adult thymi, the heterogeneity of thymus-colonizing cells that contribute to development of the T cell pool is complex and poorly understood. In this study, in conjunction with lineage potential assays, we perform phenotypic and genetic analyses on thymus-settling progenitors (TSP) isolated from the embryonic mouse thymus anlagen and surrounding perithymic mesenchyme, including simultaneous gene expression analysis of 14 hemopoietic regulators using single-cell multiplex RT-PCR. We show that, despite the known importance of CCL25-CCR9 mediated thymic recruitment of T cell progenitors, embryonic PIR(+)c-Kit(+) TSP can be subdivided into CCR9(+) and CCR9(-) subsets that differ in their requirements for a functional thymic microenvironment for thymus homing. Despite these differences, lineage potential studies of purified CCR9(+) and CCR9(-) TSP reveal a common bias toward T cell-committed progenitors, and clonal gene expression analysis reveals a genetic consensus that is evident between and within single CCR9(+) and CCR9(-) TSP. Collectively, our data suggest that although the earliest T cell progenitors may display heterogeneity with regard to their requirements for thymus colonization, they represent a developmentally homogeneous progenitor pool that ensures the efficient generation of the first cohorts of T cells during thymus development.

Background/aims: Non-cirrhotic intrahepatic portal hypertension (NCIPH) is generally regarded to have a benign prognosis. We have studied a cohort followed-up at a tertiary referral center and postulate that gut-derived prothrombotic factors may contribute to the pathogenesis and prognosis of NCIPH., Methods: We retrospectively analyzed prognostic indicators in 34 NCIPH patients. We also searched for associated gut diseases., Results: Transplant-free survival in NCIPH patients from first presentation with NCIPH at 1, 5, and 10 years was 94% (SE: 4.2%), 84% (6.6%), and 69% (9.8%), respectively. Decompensated liver disease occurred in 53% of patients. Three (9%) patients had ulcerative colitis while five of 31 (16%) tested had celiac disease and on Kaplan-Meier analysis, celiac disease predicted reduced transplant-free survival (p=0.018). On multivariable Cox regression analysis, independent predictors of reduced transplant-free survival were older age at first presentation with NCIPH, hepatic encephalopathy, and portal vein thrombosis. Prevalence of elevated initial serum IgA anticardiolipin antibody (CLPA) was significantly higher in NCIPH (36% of patients tested), compared to Budd-Chiari syndrome (6%) (p=0.032, Fisher's exact test) and celiac disease without concomitant liver disease (0%) (p=0.007)., Conclusions: We have identified prognostic factors and report progression to liver failure in 53% of NCIPH patients followed-up at our center. Our data supports a role for intestinal disease in the pathogenesis of intrahepatic portal vein occlusion leading to NCIPH.

The thymic medulla represents a key site for the induction of T cell tolerance. In particular, autoimmune regulator (Aire)-expressing medullary thymic epithelial cells (mTECs) provide a spectrum of tissue-restricted Ags that, through both direct presentation and cross-presentation by dendritic cells, purge the developing T cell repertoire of autoimmune specificities. Despite this role, the mechanisms of Aire(+) mTEC development remain unclear, particularly those stages that occur post-Aire expression and represent mTEC terminal differentiation. In this study, in mouse thymus, we analyze late-stage mTEC development in relation to the timing and requirements for Aire and involucrin expression, the latter a marker of terminally differentiated epithelium including Hassall's corpuscles. We show that Aire expression and terminal differentiation within the mTEC lineage are temporally separable events that are controlled by distinct mechanisms. We find that whereas mature thymocytes are not essential for Aire(+) mTEC development, use of an inducible ZAP70 transgenic mouse line--in which positive selection can be temporally controlled--demonstrates that the emergence of involucrin(+) mTECs critically depends upon the presence of mature single positive thymocytes. Finally, although initial formation of Aire(+) mTECs depends upon RANK signaling, continued mTEC development to the involucrin(+) stage maps to activation of the LTα-LTβR axis by mature thymocytes. Collectively, our results reveal further complexity in the mechanisms regulating thymus medulla development and highlight the role of distinct TNFRs in initial and terminal differentiation stages in mTECs.

While IL-4 directs CD4 T cells to produce Th2 cytokines (including IL-4, IL-13, IL-5) in vitro it has been shown that production of these cytokines can be induced in vivo in the absence of IL-4/IL-13/STAT-6 signaling. The present report shows that CD8 as well as CD4 T cells activated through their TCR, in vitro upregulate the Th2-features - IL-4, IL-13, IL-5, and GATA-3. However, in vivo while alum-precipitated antigen strongly and selectively induces these Th2-features in CD4 T cells, CD8 T cells mount a markedly different response to this antigen. This CD8 response is associated with strong proliferation and production of IFN-gamma, but no Th2-features are induced. Alum-protein formulations are widely used in human vaccines and typically induce strong antibody responses characterized by the differentiation of IL-4-producing CD4 T cells and immunoglobulin class switching to IgG1. Nevertheless, the mechanism responsible for CD4 Th2 and follicular helper T cell commitment triggered by these alum-protein vaccines is still poorly understood. Analysis of the in vivo response to alum-precipitated protein shows that while subsets of CD4 T cells strongly upregulate Th2 and follicular helper T cell features including the surface markers OX40, CXCR5, PD-1, IL-17RB and the transcription factor c-Maf, CD8 T cells do not. These discrete differences between responding CD4 and CD8 T cells provide further insight into the differences between Th2 polarization of CD4 T cells directed by IL-4 in vitro and the induction of IL-4 production by CD4 T cells in vivo in response to alum-precipitated protein.

Lymphoid tissue inducer cells (LTi) play an important role in the development of lymphoid tissue in embryos. Adult CD4(+)CD3(-) LTi-like cells present a similar phenotype and gene expression to their embryonic counterpart and have important roles in CD4(+) T-cell memory and lymphoid tissue recovery following viral infection. However, adult LTi-like cells are heterogeneous populations and the factors that regulate their survival and accumulation within secondary lymphoid organs remain unclear, in particular whether the T-zone stroma is involved. Here we report the identification and characterization of a distinct subset of podoplanin(+) murine splenic stromal cells that support adult LTi-like cell survival. We have identified and isolated CD45(-)podoplanin(+) stromal cell populations which have a similar but distinct phenotype to T-zone reticular cells in LN. CD45(-)podoplanin(+) fibroblast-like cells mediate LTi-like cell survival in vitro; surprisingly this was not dependent upon IL-7 as revealed through blocking Ab experiments and studies using LTi-like cells unable to respond to gamma chain cytokines. Our findings show that adult LTi-like cells require extrinsic signals from podoplanin(+) splenic stromal cells to survive and suggest that IL-7 is not necessary to mediate their survival in the adult spleen.

Phylogeny indicates that in mammals memory CD4-dependent antibody responses evolved after monotremes split from the common ancestor of marsupial and eutherian mammals. This was strongly associated with the development of segregated B and T cell areas and the development of a linked lymph node network. The evolution of the lymphotoxin beta receptor in these higher mammals was key to the development of these new functions. Here, we argue that lymphoid tissue inducer cells played a pivotal role not only in the development of organized lymphoid structures but also in the subsequent genesis of the CD4-dependent class-switched memory antibody responses that depend on an organized infrastructure to work. In this review, we concentrate on the role of this cell type in the making of a tolerant CD4 T cell repertoire and in the sustenance of CD4 T cell responses for protective immunity., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Phylogeny indicates that adaptive immunity evolved first in diffusely distributed lymphoid tissues found in the lamina propria (LP) of the gut. B follicular structures appeared later, probably initially in isolated lymphoid follicles in the LP and then in organized lymphoid tissues such as lymph nodes and Peyer's patches. The development of these new lymphoid structures was enabled by gene duplication and evolution of new tumor necrosis family members. Here, we argue that lymphoid tissue inducer cells (LTis) had a pivotal role, not only in the development of organized lymphoid structures, but also in the subsequent genesis of the CD4-dependent class-switched memory antibody responses. In this review, we concentrate on the latter function: the sustenance by LTis of CD4 T-cell responses for protective immunity.

The pathogenic outcomes of viral infection are often reminiscent of a dysfunctional immune system. Thus, cytomegalovirus (CMV) causes disruption of the lymphoid architecture and the functionality of lymphocytes, both of which are features of CD30 deficiency. It was therefore plausible that CD30 might interfere with CMV infection. The present study identifies CD30 as an inducible NK-cell receptor critical for innate immunity against CMV. Expression of CD30 integrates survival signals to NK cells that allow them to prevent viral spread and subsequent disintegration of secondary lymphoid tissue. Deficiency in CD30 results in exaggerated NK cell death and complete abrogation of the lymphoid architecture. Our data define the necessity of NK cells for protection of secondary lymphoid organs and describe a mechanism by which this protection is conferred.