Two prototypic types of virus-specific CD8(+) T cells can be found in latently infected individuals: CD45R0(+)CD27(+)CCR7(-) effector-memory, and CD45RA(+)CD27(-)CCR7(-) effector-type cells. It has ...recently been implied that CD45RA(+)CD27(-)CCR7(-) T cells are terminally differentiated effector cells and as such have lost all proliferative capacity. We show in this study, however, that stimulation of CMV-specific CD45RA(+)CD27(-)CCR7(-) T cells with their cognate peptide in concert with either CD4(+) help or IL-2, IL-15, or IL-21 in fact induces massive clonal expansion. Concurrently, these stimulated effector T cells change cell surface phenotype from CD45RA to CD45R0 and regain CCR7, while effector functions are maintained. Our data imply that CD45RA(+)CD27(-)CCR7(-) effector-type T cells contribute to immunity not only by direct execution of effector functions, but also by yielding progeny in situations of viral reinfection or reactivation.
In the atmosphere, microphysics refers to the microscale processes that affect cloud and precipitation particles and is a key linkage among the various components of Earth's atmospheric water and ...energy cycles. The representation of microphysical processes in models continues to pose a major challenge leading to uncertainty in numerical weather forecasts and climate simulations. In this paper, the problem of treating microphysics in models is divided into two parts: (i) how to represent the population of cloud and precipitation particles, given the impossibility of simulating all particles individually within a cloud, and (ii) uncertainties in the microphysical process rates owing to fundamental gaps in knowledge of cloud physics. The recently developed Lagrangian particle‐based method is advocated as a way to address several conceptual and practical challenges of representing particle populations using traditional bulk and bin microphysics parameterization schemes. For addressing critical gaps in cloud physics knowledge, sustained investment for observational advances from laboratory experiments, new probe development, and next‐generation instruments in space is needed. Greater emphasis on laboratory work, which has apparently declined over the past several decades relative to other areas of cloud physics research, is argued to be an essential ingredient for improving process‐level understanding. More systematic use of natural cloud and precipitation observations to constrain microphysics schemes is also advocated. Because it is generally difficult to quantify individual microphysical process rates from these observations directly, this presents an inverse problem that can be viewed from the standpoint of Bayesian statistics. Following this idea, a probabilistic framework is proposed that combines elements from statistical and physical modeling. Besides providing rigorous constraint of schemes, there is an added benefit of quantifying uncertainty systematically. Finally, a broader hierarchical approach is proposed to accelerate improvements in microphysics schemes, leveraging the advances described in this paper related to process modeling (using Lagrangian particle‐based schemes), laboratory experimentation, cloud and precipitation observations, and statistical methods.
Plain Language Summary
In the atmosphere, microphysics—the small‐scale processes affecting cloud and precipitation particles such as their growth by condensation, evaporation, and melting—is a critical part of Earth's weather and climate. Because it is impossible to simulate every cloud particle individually owing to their sheer number within even a small cloud, atmospheric models have to represent the evolution of particle populations statistically. There are critical gaps in knowledge of the microphysical processes that act on particles, especially for atmospheric ice particles because of their wide variety and intricacy of their shapes. The difficulty of representing cloud and precipitation particle populations and knowledge gaps in cloud processes both introduce important uncertainties into models that translate into uncertainty in weather forecasts and climate simulations, including climate change assessments. We discuss several specific challenges related to these problems. To improve how cloud and precipitation particle populations are represented, we advocate a “particle‐based” approach that addresses several limitations of traditional approaches and has recently gained traction as a tool for cloud modeling. Advances in observations, including laboratory studies, are argued to be essential for addressing gaps in knowledge of microphysical processes. We also advocate using statistical modeling tools to improve how these observations are used to constrain model microphysics. Finally, we discuss a hierarchical approach that combines the various pieces discussed in this article, providing a possible blueprint for accelerating progress in how microphysics is represented in cloud, weather, and climate models.
Key Points
Microphysics is an important component of weather and climate models, but its representation in current models is highly uncertain
Two critical challenges are identified: representing cloud and precipitation particle populations and knowledge gaps in cloud physics
A possible blueprint for addressing these challenges is proposed to accelerate progress in improving microphysics schemes
We have studied the reconstitution of the T-cell compartment after bone marrow transplantation (BMT) in five patients who received a graft-versus-host disease (GVHD) prophylaxis consisting of ...methotrexate, cyclosporin, and 10 daily injections (day -4 to day +5) of Campath-1G. This treatment eliminated virtually all T cells (7 +/- 8 T cells/microL at day 14) which facilitated the analysis of the thymus-dependent and independent pathways of T-cell regeneration. During the first 6 months, the peripheral T-cell pool was repopulated exclusively through expansion of residual T cells with all CD4(+) T cells expressing the CD45RO-memory marker. In two patients, the expansion was extensive and within 2 months, the total number of T cells (CD8>>CD4) exceeded 1,000/microL. In the other three patients, T cells remained low (87 +/- 64 T cells/microL at 6 months) and remained below normal values during the 2 years of the study. In all patients, the first CD4(+)CD45RA+RO- T cells appeared after 6 months and accumulated thereafter. In the youngest patient (age 13), the increase was relatively fast and naive CD4(+) T cells reached normal levels (600 T cells/microL) 1 year later. In the four adult patients (age 25 +/- 5), the levels reached at that time-point were significantly lower (71 +/- 50 T cells/microL). In all patients, the T-cell repertoire that had been very limited, diversified with the advent of the CD4(+)CD45RA+RO- T cells. Cell sorting experiments showed that this could be attributed to the complexity of the T-cell repertoire of the CD4(+)CD45RA+RO- T cells that was comparable to that of a normal individual and that, therefore, it is likely that these cells are thymic emigrants. We conclude that after BMT, the thymus is essential for the restoration of the T-cell repertoire. Because the thymic activity is restored with a lag time of approximately 6 months, this might explain why, in particular in recipients of a T-cell-depleted graft, immune recovery is delayed.
In normal lymphoid tissues the tumour necrosis factor‐receptor family member CD27 and its ligand CD70 have a restricted expression pattern. Previously, we reported that expression of CD27 is ...deregulated in B‐cell leukaemias and lymphomas. Here we show that, although infrequently expressed by normal human B cells in vivo, CD70 is found on 50% of B‐CLLs, 33% of follicle centre lymphomas, 71% of large B‐cell lymphomas, and 25% of mantle cell lymphomas. Interestingly, in the majority of leukaemias and lymphomas examined, CD70 was found to have a capped appearance, a feature that coincided with co‐expression of CD27. Functional analysis showed that a subset of B‐CLLs could proliferate vigorously in response to CD70 mAb but not to CD27 mAb. This response was synergistically enhanced by ligation of CD40 but inhibited by the presence of IL‐4. Additional experiments indicated that the proliferative response was due to an agonistic signal delivered via CD70, rather than blocking of negative signalling by CD27. Thus, next to its role as ligand, in a subset of malignant B cells CD70 can operate as receptor and as such might contribute to progression of these B‐cell malignancies.
Human CD8+ memory- and effector-type T cells are poorly defined. We show here that, next to a naive compartment, two discrete primed subpopulations can be found within the circulating human CD8+ T ...cell subset. First, CD45RA-CD45R0(+) cells are reminiscent of memory-type T cells in that they express elevated levels of CD95 (Fas) and the integrin family members CD11a, CD18, CD29, CD49d, and CD49e, compared to naive CD8+ T cells, and are able to secrete not only interleukin (IL) 2 but also interferon gamma, tumor necrosis factor alpha, and IL-4. This subset does not exert cytolytic activity without prior in vitro stimulation but does contain virus-specific cytotoxic T lymphocyte (CTL) precursors. A second primed population is characterized by CD45RA expression with concomitant absence of expression of the costimulatory molecules CD27 and CD28. The CD8+CD45RA+CD27- population contains T cells expressing high levels of CD11a, CD11b, CD18, and CD49d, whereas CD62L (L-selectin) is not expressed. These T cells do not secrete IL-2 or -4 but can produce IFN-gamma and TNF-alpha. In accordance with this finding, cells contained within this subpopulation depend for proliferation on exogenous growth factors such as IL-2 and -15. Interestingly, CD8+CD45RA+CD27- cells parallel effector CTLs, as they abundantly express Fas-ligand mRNA, contain perforin and granzyme B, and have high cytolytic activity without in vitro prestimulation. Based on both phenotypic and functional properties, we conclude that memory- and effector-type T cells can be separated as distinct entities within the human CD8+ T cell subset.
SUMMARY
Reduced serum IgG and subclass levels have been demonstrated in children with chronic renal failure. To study possible causes of this reduction, we analysed B cell subset composition, T ...helper cell frequencies and immunoglobulin (Ig) production capacity in vitro in children with chronic renal failure, with or without dialysis treatment. B cell subsets were characterized by determining CD27, IgM, IgD and CD5 expression within the CD19+ population. Intracellular expression of interferon (IFN)‐γ, interleukin (IL)‐2 and IL‐4 in PMA/ionomycin‐stimulated peripheral blood mononuclear cells (PBMC) was used to evaluate T helper frequencies. The capacity of B cells to secrete Ig in vitro was determined by measuring IgG1, IgG2 and IgM in culture supernatants of anti‐CD2/CD28 monoclonal antibody (MoAb)‐ or SAC/IL‐2‐stimulated PBMC. Memory B cell numbers (identified as percentage or absolute number of CD19+ IgM¯IgD¯ or CD19+CD27+ lymphocytes) were lower in children treated with haemodialysis (HD), peritoneal dialysis (PD) and children with chronic renal failure before starting dialysis treatment (CRF) compared to healthy controls (HC) (P < 0·05). Compared with HC, CD5+ (naive) B cells were reduced in HD‐treated patients but not for PD or for children with chronic renal failure before starting dialysis treatment (CRF). No significant differences in CD4+ T helper cell subsets were found between the groups. However, CRF children had a higher percentage of IFN‐γ producing CD8+ T lymphocytes compared to HC (P = 0·02). Finally, IgG1, IgG2 and IgM production in vitro was similar in the four groups. In conclusion, significantly lower numbers of memory type B cells were found in children with chronic renal failure compared to healthy controls. This reduction may contribute to the low Ig levels found in these children.
Kawasaki disease (KD), an acute febrile disease in children of unknown etiology, is characterized by a vasculitis that may result in coronary artery aneurysms (CAAs). In new patients with KD, a ...selective and prolonged T cell unresponsiveness to activation via the T cell antigen receptor CD3 was observed, whereas proliferation to other stimuli was intact. This “split T cell anergy” delineated KD from other pediatric infections and autoimmune diseases and correlated with CAA formation (P < .001). A transient immune dysfunction was also suggested by an incomplete responsiveness to measles-mumps-rubella (MMR) vaccination in patients with KD versus controls (P < .0001; odds ratio, 15.6; 95% confidence interval, 4.8–51.1), which was overcome by revaccination(s). The reduced responsiveness to MMR in patients with KD suggests a subtle and predetermining immune dysfunction. An inherent immaturity to clear certain antigens may be an important cause that precipitates KD and the immune dysregulation during acute disease.
GPR56 belongs to a new cluster of adhesion‐GPCRs on human immune cells and is expressed with high specificity by cytotoxic lymphocytes.
We here report the existence of a new cluster of adhesion‐GPCRs ...in human immune cells. Analysis of a comprehensive immune cell transcriptome dataset indicated that expression of the closely related receptors, GPR56, GPR97, and GPR114, is associated with single lymphocyte and granulocyte subsets. Applying flow cytometric analysis with newly generated mAb, we show that expression of GPR56 is restricted to cytotoxic NK and T lymphocytes, including CD8+, CD4+, and γδ T cells. Primary infection with human CMV, which generates a vast population of CD8+ T cells with an effector phenotype, induced a strong increase in GPR56 expression in virus‐specific CD8+ T cells that remained detectable during latency. In NK‐92 cells, ectopic expression of GPR56 inhibited spontaneous and SDF‐1‐stimulated cell migration. Our data suggest that GPR56 expression is a common trait of human cytotoxic lymphocytes and might affect the migratory properties of these cells.
The objective of this study was to determine whether a suite of wood quantity and quality attributes of balsam fir and black spruce forests could be predicted using airborne laser scanner data. In ...situ estimates of stand structure and wood fibre attributes were derived from measurements at sample plots covering a wide range of forest conditions of insular Newfoundland. Models developed to predict field estimates explained 52–90 per cent of the variation in structure attributes, including mean and quadratic mean diameter at breast height, average and dominant height, stem density, basal area, total and merchantable volume and above-ground total biomass. Cross-validated root mean square errors were <24 per cent of mean values, with the exception of stem density, for which errors were 27–32 per cent. Models of fibre attributes explained 18–53 per cent of the variation in fibre length, wood density, radial diameter, coarseness, microfibril angle, modulus of elasticity, wall thickness and specific surface with cross-validated root mean square errors of <14 per cent of mean values. Similar results were achieved for fibre attribute models derived using geographic, climate and vegetation variables. The results demonstrate potential for inventory of quantity and quality attributes over a large region of boreal forests in Newfoundland, Canada.
► Activated sludge (AS) samples were taken from ten different membrane bioreactors. ► Correlations with AS filterability and AS characteristics were assessed. ► AS filterability cannot be attributed ...to a single activated sludge parameter. ► Deflocculation and low hydrophobicity negatively impact sludge filterability. ►
Bioflocculation state is a major indicator for activated sludge filterability.
In the field of membrane bioreactors (MBRs) many membrane fouling related questions still remain unanswered. The goal of this research is to unveil some of the black-box features of activated sludge filterability by correlating the results from activated sludge filterability measurements following the Delft Filtration Characterization method (DFCm) with a large set of activated sludge characteristics. Ten different MBRs in Belgium and the Netherlands were sampled in both winter and summer. All samples were subjected to the DFCm, automated image analysis and an extensive set of standardized measurements. No clear correlation could be found between a single sludge parameter and activated sludge filterability. However, a combination of sludge morphology and relative hydrophobicity (RH) allows for a clear classification of activated sludge into two classes, i.e.,
bad and
poor to good, implying that deflocculation and a low RH have a negative impact on activated sludge filterability. Furthermore, for sludge samples having
poor to good filterability, accurate estimations of sludge filterability can be made when including more parameters. The main conclusion is that filterability can be predicted by analyzing the
bioflocculation state of the activated sludge.
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