Foxp3(+) regulatory T cells (T(reg) cells) maintain immunological tolerance, and their deficiency results in fatal multiorgan autoimmunity. Although heightened signaling via the T cell antigen ...receptor (TCR) is critical for the differentiation of T(reg) cells, the role of TCR signaling in T(reg) cell function remains largely unknown. Here we demonstrated that inducible ablation of the TCR resulted in T(reg) cell dysfunction that could not be attributed to impaired expression of the transcription factor Foxp3, decreased expression of T(reg) cell signature genes or altered ability to sense and consume interleukin 2 (IL-2). Instead, TCR signaling was required for maintaining the expression of a limited subset of genes comprising 25% of the activated T(reg) cell transcriptional signature. Our results reveal a critical role for the TCR in the suppressor capacity of T(reg) cells.
Regulatory T cells (T
cells), which have abundant expression of the interleukin 2 receptor (IL-2R), are reliant on IL-2 produced by activated T cells. This feature indicates a key role for a simple ...network based on the consumption of IL-2 by T
cells in their suppressor function. However, congenital deficiency in IL-2R results in reduced expression of the T
cell lineage-specification factor Foxp3, which has confounded experimental efforts to understand the role of IL-2R expression and signaling in the suppressor function of T
cells. Using genetic gain- and loss-of-function approaches, we found that capture of IL-2 was dispensable for the control of CD4
T cells but was important for limiting the activation of CD8
T cells, and that IL-2R-dependent activation of the transcription factor STAT5 had an essential role in the suppressor function of T
cells separable from signaling via the T cell antigen receptor.
The Arabian Sea is an important moisture source for Indian monsoon rainfall. The skill of climate models in simulating the monsoon and its variability varies widely, while Arabian Sea cold sea ...surface temperature (SST) biases are common in coupled models and may therefore influence the monsoon and its sensitivity to climate change. We examine the relationship between monsoon rainfall, moisture fluxes and Arabian Sea SST in observations and climate model simulations. Observational analysis shows strong monsoons depend on moisture fluxes across the Arabian Sea, however detecting consistent signals with contemporaneous summer SST anomalies is complicated in the observed system by air/sea coupling and large-scale induced variability such as the El Niño-Southern Oscillation feeding back onto the monsoon through development of the Somali Jet. Comparison of HadGEM3 coupled and atmosphere-only configurations suggests coupled model cold SST biases significantly reduce monsoon rainfall. Idealised atmosphere-only experiments show that the weakened monsoon can be mainly attributed to systematic Arabian Sea cold SST biases during summer and their impact on the monsoon-moisture relationship. The impact of large cold SST biases on atmospheric moisture content over the Arabian Sea, and also the subsequent reduced latent heat release over India, dominates over any enhancement in the land-sea temperature gradient and results in changes to the mean state. We hypothesize that a cold base state will result in underestimation of the impact of larger projected Arabian Sea SST changes in future climate, suggesting that Arabian Sea biases should be a clear target for model development.
Infection triggers expansion and effector differentiation of T cells specific for microbial antigens in association with metabolic reprograming. We found that the glycolytic enzyme lactate ...dehydrogenase A (LDHA) is induced in CD8
T effector cells through phosphoinositide 3-kinase (PI3K) signaling. In turn, ablation of LDHA inhibits PI3K-dependent phosphorylation of Akt and its transcription factor target Foxo1, causing defective antimicrobial immunity. LDHA deficiency cripples cellular redox control and diminishes adenosine triphosphate (ATP) production in effector T cells, resulting in attenuated PI3K signaling. Thus, nutrient metabolism and growth factor signaling are highly integrated processes, with glycolytic ATP serving as a rheostat to gauge PI3K-Akt-Foxo1 signaling in the control of T cell immunity. Such a bioenergetic mechanism for the regulation of signaling may explain the Warburg effect.
ERA-Interim reanalysis data from the past 35 years have been used with a newly developed feature tracking algorithm to identify Indian monsoon depressions originating in or near the Bay of Bengal. ...These were then rotated, centralized, and combined to give a fully three-dimensional 106-depression composite structure—a considerably larger sample than any previous detailed study on monsoon depressions and their structure. Many known features of depression structure are confirmed, particularly the existence of a maximum to the southwest of the center in rainfall and other fields and a westward axial tilt in others. Additionally, the depressions are found to have significant asymmetry owing to the presence of the Himalayas, a bimodal midtropospheric potential vorticity core, a separation into thermally cold (~−1.5 K) and neutral (~0 K) cores near the surface with distinct properties, and the center has very large CAPE and very small CIN. Variability as a function of background state has also been explored, with land–coast–sea, diurnal, ENSO, active–break, and Indian Ocean dipole contrasts considered. Depressions are found to be markedly stronger during the active phase of the monsoon, as well as during La Niña. Depressions on land are shown to be more intense and more tightly constrained to the central axis. A detailed schematic diagram of a vertical cross section through a composite depression is also presented, showing its inherent asymmetric structure.
FOXP3(+) regulatory T cells (Treg cells) prevent autoimmunity by limiting the effector activity of T cells that have escaped thymic negative selection or peripheral inactivation. Despite the ...information available about molecular factors mediating the suppressive function of Treg cells, the relevant cellular events in intact tissues remain largely unexplored, and whether Treg cells prevent activation of self-specific T cells or primarily limit damage from such cells has not been determined. Here we use multiplex, quantitative imaging in mice to show that, within secondary lymphoid tissues, highly suppressive Treg cells expressing phosphorylated STAT5 exist in discrete clusters with rare IL-2-positive T cells that are activated by self-antigens. This local IL-2 induction of STAT5 phosphorylation in Treg cells is part of a feedback circuit that limits further autoimmune responses. Inducible ablation of T cell receptor expression by Treg cells reduces their regulatory capacity and disrupts their localization in clusters, resulting in uncontrolled effector T cell responses. Our data thus reveal that autoreactive T cells are activated to cytokine production on a regular basis, with physically co-clustering T cell receptor-stimulated Treg cells responding in a negative feedback manner to suppress incipient autoimmunity and maintain immune homeostasis.
Adaptive immune responses are tailored to different types of pathogens through differentiation of naive CD4 T cells into functionally distinct subsets of effector T cells (T helper 1 (T
1), T
2, and ...T
17) defined by expression of the key transcription factors T-bet, GATA3, and RORγt, respectively. Regulatory T (T
) cells comprise a distinct anti-inflammatory lineage specified by the X-linked transcription factor Foxp3 (refs 2, 3). Paradoxically, some activated T
cells express the aforementioned effector CD4 T cell transcription factors, which have been suggested to provide T
cells with enhanced suppressive capacity. Whether expression of these factors in T
cells-as in effector T cells-is indicative of heterogeneity of functionally discrete and stable differentiation states, or conversely may be readily reversible, is unknown. Here we demonstrate that expression of the T
1-associated transcription factor T-bet in mouse T
cells, induced at steady state and following infection, gradually becomes highly stable even under non-permissive conditions. Loss of function or elimination of T-bet-expressing T
cells-but not of T-bet expression in T
cells-resulted in severe T
1 autoimmunity. Conversely, following depletion of T-bet
T
cells, the remaining T-bet
cells specifically inhibited T
1 and CD8 T cell activation consistent with their co-localization with T-bet
effector T cells. These results suggest that T-bet
T
cells have an essential immunosuppressive function and indicate that T
cell functional heterogeneity is a critical feature of immunological tolerance.
Many climate models have problems simulating Indian summer monsoon rainfall and its variability, resulting in considerable uncertainty in future projections. Problems may relate to many factors, such ...as local effects of the formulation of physical parametrisation schemes, while common model biases that develop elsewhere within the climate system may also be important. Here we examine the extent and impact of cold sea surface temperature (SST) biases developing in the northern Arabian Sea in the CMIP5 multi-model ensemble, where such SST biases are shown to be common. Such biases have previously been shown to reduce monsoon rainfall in the Met Office Unified Model (MetUM) by weakening moisture fluxes incident upon India. The Arabian Sea SST biases in CMIP5 models consistently develop in winter, via strengthening of the winter monsoon circulation, and persist into spring and summer. A clear relationship exists between Arabian Sea cold SST bias and weak monsoon rainfall in CMIP5 models, similar to effects in the MetUM. Part of this effect may also relate to other factors, such as forcing of the early monsoon by spring-time excessive equatorial precipitation. Atmosphere-only future time-slice experiments show that Arabian Sea cold SST biases have potential to weaken future monsoon rainfall increases by limiting moisture flux acceleration through non-linearity of the Clausius–Clapeyron relationship. Analysis of CMIP5 model future scenario simulations suggests that such effects are small compared to other sources of uncertainty, although models with large Arabian Sea cold SST biases may suppress the range of potential outcomes for changes to future early monsoon rainfall.
Social media is increasingly used for social protest, but does internet-enabled action lead to ‘slacktivism’ or promote increased activism? We show that the answer to this question depends on prior ...level of activism, and on beliefs about the effectiveness of individual contribution to the collective campaign. Internet-enabled action was varied quasi-experimentally, with participants (n = 143) choosing whether or not to share a campaign on social media. Participants were then informed that sharing on social media had a big (high action efficacy) or small (low action efficacy) impact on achieving the campaign's goal. Prior levels of activism were measured before the experiment, and general levels of collective action were measured one week after the experiment. Taking internet-enabled action for one campaign increased future activism for other campaigns – but only in individuals who were already active and who perceived their actions to be an effective contribution to the campaign.
•We show online collective action for one cause can facilitate future action for other social issues.•We identify the conditions under which ‘slacktivism’ occurs and when a facilitation effect occurs.•We find that online action can inhibit future action for the same cause.•When perceived as effective, online action aids cross-domain action in those with more experience.
There is no consensus on the treatment of irreparable massive rotator cuff tears. The goal of this systematic review and meta-analysis was to (1) compare patient-reported outcome scores, (2) define ...failure and reoperation rates, and (3) quantify the magnitude of patient response across treatment strategies.
The MEDLINE, Embase, CENTRAL (Cochrane Central Register of Controlled Trials), and Scopus databases were searched for studies including physical therapy and operative treatment of massive rotator cuff tears. The criteria of the Methodological Index for Non-randomized Studies were used to assess study quality. Primary outcome measures were patient-reported outcome scores as well as failure, complication, and reoperation rates. To quantify patient response to treatment, we compared changes in the Constant-Murley score and American Shoulder and Elbow Surgeons (ASES) score with previously reported minimal clinically important difference (MCID) thresholds.
No level I or II studies that met the inclusion and exclusion criteria were found. Physical therapy was associated with a 30% failure rate among the included patients, and another 30% went on to undergo surgery. Partial repair was associated with a 45% retear rate and 10% reoperation rate. Only graft interposition was associated with a weighted average change that exceeded the MCID for both the Constant-Murley score and ASES score. Latissimus tendon transfer techniques using humeral bone tunnel fixation were associated with a 77% failure rate. Superior capsular reconstruction with fascia lata autograft was associated with a weighted average change that exceeded the MCID for the ASES score. Reverse arthroplasty was associated with a 10% prosthesis failure rate and 8% reoperation rate.
There is a lack of high-quality comparative studies to guide treatment recommendations. Compared with surgery, physical therapy is associated with less improvement in perceived functional outcomes and a higher clinical failure rate.
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