In contrast, a recent registry analysis of the Organ Procurement and Transplantation Network (OPTN) showed that in renal transplant recipients maintained on tacrolimus and mycophenolate mofetil, recipients receiving basiliximab induction had significantly lower risk of triple end-points of acute rejection,

graft failure or death compared with no induction only if steroids were present at discharge (adjusted odds ratio (OR) 0.82, 95% CI 0.74, 0.92), but was not significantly different 5-Fluoracil research buy if steroids were absent on discharge (adjusted OR 0.69, 95% CI 0.42, 1.11).18 In our study, the lack of association between IL-2Ra induction and rejection in tacrolimus-treated recipients may be partly explained by the possibility of numbers too small to detect any differences (n = 767 compared with n = 11 164 in OPTN

analysis) and/or residual confounders. In addition, the choice to use induction therapy and/or initial CNI is often dependent on transplanting centres’ preferences, which is not collected by registry data. Our study has certain limitations. First, retrospective cohort studies are subjected to potential biases such as differing practices in the use of IL-2Ra between transplanting centres, even if these factors were accounted Bortezomib clinical trial for in the adjusted models. Nevertheless, there may be residual and unmeasured confounders in registry analyses that could have potentially affected our findings. Second, we had arbitrarily stratified recipients into low- and intermediate-risk recipients based on three factors – HLA-matching, PRA levels and transplant number, all of which have been shown to independently affect graft and patient

outcomes.19–21 We acknowledged that there are other factors that would define recipients’ immunological risk heptaminol including donor and recipient age, even though these are adjusted for in the multivariate models. Although this registry study does not directly provide evidence of causality, it does provide support for clinical studies of similar nature. Future trials will need to further define the role of IL-2Ra by addressing the benefit of IL-2Ra in renal transplant recipients with differing immunological risk in the era of novel and more potent immunosuppressive therapy (including cyclosporine, tacrolimus and sirolimus/everolimus-based therapy). In conclusion, the use of IL-2Ra in intermediate-risk recipients is associated with reduced rejection risk in cyclosporine-treated patients, but this does not translate to an improvement in graft or patient survival. There was no association between IL-2Ra and graft outcomes in low-risk recipients.

[9] These Guidelines favour an approach of improving net clinical outcome by reducing bleeding risk in patients assessed to be at high risk of bleeding, a marker for which is renal dysfunction (eGFR < 60 mL/min). There is a perceived risk of increase bleeding in CKD patients that has led to other renal guideline groups recommending PCI over thrombolysis but with ungraded evidence; however, KHA-CARI have assigned a 1D grading reflecting the general population guidelines. a. We recommend that blood

pressure targets in people with CKD should be determined on an individual basis taking into account a range of patient factors including baseline risk, albuminuria level, tolerability and starting blood pressure learn more levels (1C). g. We recommend that blood pressure should be lowered in individuals with CKD receiving dialysis who have suboptimal blood pressure levels (1C), and in the absence of specific data, suggest a similar target to the general population where possible (2D). There is little evidence about the efficacy in preventing CVD of different combinations of blood pressure (BP)-lowering drugs in people with CKD. If BP targets are not met, the choice of a second agent should be based on individual

patient factors, tolerability, and side-effects (ungraded). The choice of blood pressure lowering agent should be made on the grounds of individual patient variables, comorbidities, tolerability and side-effect profiles (ungraded). Individuals with CKD are at significantly increased JQ1 manufacturer risk for cardiovascular events.[1] Blood pressure is an important determinant of cardiovascular risk in the general population in which interventions that lower BP have been clearly shown to prevent

cardiovascular events.[2] Blood pressure levels are commonly elevated in people with CKD raising the possibility that BP lowering may offer significant benefit in this group.[3, 4] The objective of this guideline is to evaluate the evidence of different BP-lowering regimens in preventing CVD in patients with CKD. There click here are three main questions: What is the evidence that BP lowering is effective at reducing cardiovascular risk in patients with CKD? What is the evidence for different treatment regimens in terms of their efficacy at reducing CVD risk in patients with evidence of kidney disease? What BP target should clinicians aim for in treating patients? Randomized controlled trials in CKD populations evaluating the benefit risk ratio of BP-lowering regimens on cardiovascular outcomes are lacking. Recommendations in this guideline are therefore based on a synthesis of the best available evidence. Evidence from large RCTs indicates that BP lowering in individuals with impaired renal function reduces the risk of cardiovascular mortality and morbidity and total death. There is limited evidence that lower BP targets in patients with renal impairment are at reduced risk of CVD.

They were tested routinely for blood glucose levels and considered prediabetic, as their values of serum glucose on two occasions over a 24-h period did not differ significantly from those of control mice (0·9 ± 0·1 g/l, n = 42). NOD mice of 16 weeks of age used in

this study presented a reduced saliva flow rate INCB024360 (>35% reduction) compared with BALB/c control mice. Studies were conducted according to standard protocols of the Animal Care and Use Committee of the School of Exact and Natural Sciences, University of Buenos Aires. Submandibular glands were removed and transferred immediately to ice-cold RPMI-1640, 10% fetal bovine serum (FBS) for acinar cell isolation, as described previously [16]. Acinar cells were washed and seeded on flat-bottomed 24-well microtitre plates (Corning Glass, Corning, NY, USA) and incubated for 2 h at 37°C in a humidified incubator with 5% CO2 to separate immune adherent cells and viability determination [16]. When used, recombinant TNF-α (Promega, Madison, WI, USA) (5–10 ng/ml) was added to acinar cell culture for 3·5 h [reverse transcription–polymerase chain reaction (RT–PCR)] or for 6 h (annexin V staining and immunoblotting). In some experiments, cells were preincubated for 30 min with 100 nm VIP (PolyPeptide Labs, Strasbourg, France) before TNF-α addition in the presence or absence of H89

(1 µm). Macrophages were obtained by washing the peritoneal cavity with ice-cold RPMI-1640, as reported [24,25]. Cells were seeded at 5 × 105 cells/well (Corning Glass), incubated at 37°C for 2 h and washed thoroughly before co-cultures, nuclear Pexidartinib research buy Inositol monophosphatase 1 factor (NF)-κB activation or cytokine determination. Macrophages were co-cultured with freshly isolated acini or acini previously induced to apoptosis with TNF-α. Incubations were run at 37°C for the times indicated. VIP (100 nm) was added 30 min before the addition of acini. After incubation, acini were removed and macrophages were

washed with fresh medium. Haematoxylin and eosin (H&E) staining was used for phagocytosis determination [24]. Cells were collected for cytokine expression by quantitative RT–PCR (qRT–PCR) or flow cytometry analysis; nitrite production was determined by the Griess in supernatants, as described previously [24,25]. For flow cytometry, cells were stained with fluorescein isothiocyanate (FITC)-conjugated anti-F4/80 monoclonal antibody for 30 min (eBioscience, San Diego, CA, USA), fixed in 4% paraformaldehyde/phosphate-buffered saline (PBS)–2% FCS, permeabilized with 0·5% saponin (Sigma, St Louis, MO, USA) and incubated with phycoerythrin (PE)-conjugated anti-IL-10 monoclonal antibody (BD) or with the PE-conjugated immunoglobulin (Ig)G1 isotype; 10 000 events were acquired in a fluorescence activated cell sorter (FACS)Aria cytometer® and results analysed using the WinMDI software®.

54) after adjustment for age, gender, race, pre-existing coronary heart disease, mean arterial blood pressure, diabetes, glucose level, cholesterol level, smoking, body mass index, and geographic location within the study sites. In those with

no evidence of pre-existing heart disease, diabetes, or hypertension at enrollment to the study, the presence of retinopathy was associated with an almost threefold increased risk of future congestive heart failure (adjusted HR: 2.98; 1.50–5.94). Furthermore, the presence of retinopathy, in a nondiabetic cohort carries a similar mortality risk as diabetes itself after a cardiac event (HR: 2.28; 1.10–4.76), and over a sixfold increase in those with diabetes (HR: 6.69; 2.24–20.0) [38]. This may, in part, represent shared risk factors; however, the association remains only marginally reduced

after adjustment for known risk factors, suggesting that residual confounding is an unlikely explanation. However, selleck products despite these data, individuals at high risk do not get routine retinal screening [6]. There is an established Dabrafenib co-linearity in the development and progression of microvascular and macrovascular disease [10,37,73]. This is the subject of considerable studies to establish whether there is a causal effect in either direction or simply represents shared risk factors, although it is most likely to be a complex combination of bidirectional interactions. A typical example of this would be the interplay between diabetic nephropathy, metabolic syndrome, and atherosclerosis. An elevated urinary albumin excretion rate was first described as a feature of glomerulosclerosis with a poor prognosis in 1936 by Clifford Wilson and

Paul Kimmelstiel [35]. Indeed, many textbooks still refer to diabetic nephropathy as “Kimmelstiel–Wilson” syndrome. At that time, it was thought to represent local pathology within the renal microcirculation; however, it has subsequently PAK6 been recognized as a predictor of future cardiovascular events and mortality in diabetes, renal failure hypertension, and the general population at large [16,18,26,73,76]. Furthermore, it predicts survival after myocardial infarction [36] and stroke [59]. As such, urinary albumin excretion rate or its proxy, albumin:creatinine ratio, has become an accepted surrogate for microcirculatory target organ damage in hypertension, renal disease, and type 2 diabetes. Currently, there remains little debate as to the importance of albuminuria as a prognostic indicator, although consensus has not been reached regarding the threshold of “abnormality”, given that the association persists down into levels that are currently considered normal and below the sensitivity of commercially available assays [7]. The lack of a clear mechanistic pathway to explain the association between microalbuminuria and adverse cardiovascular outcomes has led many clinicians to believe that it is solely a marker of blood pressure exposure.

6 Databases searched: The terms used to define ARAS were ‘Renal Artery Obstruction’ (as a MeSH term and text word) and ‘renal artery stenosis’, ‘renovascular disease$’ and ‘renal artery occlusion$’ as text words. To define this further, the terms ‘Atherosclerosis’ and ‘Arteriosclerosis’, as both MeSH terms and text words along with text words ‘angioplasty$’ and ‘stent$’ were searched. In addition, various text words were searched to find references pertaining to distal protection devices. These were combined with the previous search, yielding 27 results. Ovid

MEDLINE (1950–April 2009) was the database searched. The Cochrane Central Register of Controlled Trials and Database of Systematic Reviews were PKC inhibitor searched for trials and reviews not indexed in Medline. In addition, the reference lists of manuscripts retrieved by the above method were manually reviewed for additional studies. Date of searches: 2 April 2009. There are no systematic reviews of randomized controlled trials comparing the use of distal protection devices with renal artery stenting to stenting alone. There has been one

www.selleckchem.com/products/3-methyladenine.html randomized controlled trial that compared renal artery stenting with and without a distal protection device (Tables 1–4).7 The ‘RESIST’ study had a 2 × 2 factorial design and randomized patients to an open-label distal protection device or not, and to double blind use of the platelet glycoprotein IIb/IIIa inhibitor abciximab or placebo. The sample

size was based on providing 80% power to detect a difference in glomerular filtration rate (GFR) of 5 mL/min per 1.73 m2 with a standard deviation of 8. The investigators required 85 participants and recruited 100 to allow for 15% loss to follow up. The primary outcome was change in GFR at 1 month measured by the 4-variable Modified Diet in Renal Disease (MDRD) equation and creatinine was measured by an isotope dilution mass spectrometry-traceable assay. In total, 390 patients were screened to achieve 100 randomized patients. Data were available for 91 patients; 5 refused follow up and 4 had insufficient sample to enable analysis. There was a significant decline in GFR in all groups except the group given the combination of distal protection device and abciximab. There was a significant interaction for these therapies at P < 0.05, indicating that the addition of Tolmetin abciximab to stenting with distal protection was more effective in preventing a decline in GFR than either therapy alone. Analysis of all patients randomized to the distal protection device demonstrated a percent change in GFR of –1 ± 28% compared with –10 ± 20% in those not receiving the device (P = 0.08). For abciximab, this was 0 ± 27% compared with –10 ± 20% in those receiving placebo (P < 0.05). This trial does not provide evidence that the use of distal protection devices prevents decline in GFR but suggests the possibility when used with abciximab.

As shown in Fig. 4c, the P-values determined by two-way anova were both < 0·001. In addition, we analysed the phosphorylation levels of STAT-3 and STAT-1 after rhIL-10 stimulation in six LN patients, seven non-LN patients and seven healthy controls. As shown in Fig. 4d, the phosphorylation levels of STAT-3 after rhIL-10 stimulation in LN patients were significantly lower than in non-LN patients and healthy controls, P < 0·05. Figure 4d also shows the average phosphorylation levels of STAT-3 in the subdivided groups according

to the SLEDAI and LN. Although the patients with selleck products simultaneously active SLE and LN disease manifested the lowest phosphorylation levels of STAT-3, the sample number was too small to perform a statistical analysis. There were no

differences in the phosphorylation levels of STAT-3 in newly diagnosed SLE patients, treated patients and healthy controls. For STAT-1, we also observed delayed phosphorylation in SLE patients; however, the phosphorylation levels were similar among controls, active patients, inactive patients, LN patients KU57788 and non-LN patients. In summary, our data suggest that IL-10 signalling is defective in patients with LN and in active SLE patients. We observed significantly higher plasma IL-6 and lower plasma IL-2 levels in all SLE patients than in healthy controls, but observed similar levels of IL-6 and IL-2 in LN and non-LN patients. Plasma IL-10 levels were significantly higher in LN patients than in controls, but not in non-LN patients. The plasma IFN-γ concentrations of patients and controls were all close to the lowest detection limit of the assay, and were not taken into consideration. The results are displayed in Table 2. There was a negative correlation between plasma IL-10 levels and IL-10R1 levels on CD4+ and CD8+ T cells, indicating that IL-10 and its receptor on T cells second may have some regulatory effect on each other.

Plasma IL-6 and IL-2 levels were not correlated with IL-10R1 expression. Plasma IL-10, IL-6 and IL-2 levels were not correlated with SLEDAI. SLE is clinically heterogeneous, and individual cytokine patterns will be more or less important to different disease manifestations and subtypes of patients [24]. In this study we investigated the expression and signalling of IL-10R1 in SLE patients to elucidate the role of the IL-10 signalling pathway in the pathogenesis of SLE. We found that the patients with LN expressed lower levels of IL-10R1 on CD4+ cells than controls and non-LN patients. The patients with LN also expressed lower levels of IL-10R1 on CD8+ cells than non-LN patients, but not lower than controls. Moreover, the expression levels of IL-10R1 on CD4+ and CD8+ T cells were correlated negatively with SLE disease activity.

The gels were either stained with silver staining or proteins were transferred to polyvinylidene fluoride (PVDF) membrane. The blots prepared from the immunoprecipitates VX-809 cost were

then probed using anti-pSyk antibodies and blots were developed using Millipore chemiluminscent substrate. After Western analysis, blots were stained with Coommasie blue R250 to ensure uniform protein loading. A total of 0·5 × 106 cells were treated with various stimuli and washed with cold PBS; cells were then fixed in 3% formaldehyde for 15 min at RT. Fixed cells were then permeabilized using 95% methanol for 30 min on ice and 10 min at −20°C. After washing, blocking was performed with 1% serum albumin (BSA) and 2·5% species-specific serum diluted in PBS at RT for 1 h. These cells were incubated further with the appropriate primary antibody at a dilution of 1 : 100 for 1 h at RT. For co-staining, a monoclonal antibody recognizing the FcγRIIIA/B and a rabbit polyclonal recognizing the pSyk was used

for staining. Subsequently cells were incubated with AlexaFluor® Rapamycin in vitro 488- and 594-conjugated secondary anti-mouse and anti-rabbit at a dilution of 1 : 200 at RT for 1 h. Co-localization for FcγRIIIA/B with pSyk was carried out using Olympus FV-1000 software. Cells were examined from three fields in three experiments in all co-localization studies. Cells were examined at ×400 and ×630 magnification in fluorescent (Leica, DM400B) or confocal microscope (Olympus, FV-1000). In certain cases optical zoom was employed to gain access to cellular details. The Olopatadine staining for co-localization of FcγRIIIA/B and intracellular FcRγ chain was essentially carried out as described in the earlier section. All serial Z-series sections were included for the analysis (Olympus FV-1000, co-localization software). To co-localize the FcγRIIIA/B, FcγRIIIB with ICs or AHG, a 5 µg/ml of AlexaFlour 488–AHG was used prior to staining of cells with anti-FcγRIIIA/B monoclonal and/or anti-FcγRIIIB antibody. Percentage staining was calculated from three independent fields by enumerating total cells, cells stained with

anti-FcγRIIIA/B and anti-FcγRIIIB. Activated cells were washed with cold PBS and resuspended in 0·1% BSA–PBS. To 1 × 106 cells, a total of 0·2 µg of CTB conjugated with FITC was added and cells were incubated for 20 min in an ice bath. Thereafter, the cells were fixed and stained for FcγRIIIA/B and mounted using SlowFade Gold anti-fade reagent containing 4′,6-diamidino-2-phenylindole (DAPI) (Molecular Probes, Eugene, OR, USA) or without DAPI when using AlexaFluor® 350 conjugate. RT–PCR was performed on the total cellular RNA using the RNA isolation kit (Agilent Technologies, Santa Clara, CA, USA). Using a total of 200 ng of the RNA, the PCR product was generated using the Access RT–PCR system (Promega, Madison, WI, USA).

[3] ‘On’ signals act to attract activated microglia to the site of injury along a chemical gradient through activation of specific receptors. Among possible chemoattractants, release of ATP upon focal brain injury triggers the rapid response of microglial processes towards the site of injury,[1] a process that involves purinergic (P2) receptors as demonstrated in vivo by the decrease in chemotactic microglial response upon application of various

BVD-523 concentration P2 receptor inhibitors directly to the cortex,[1] or through experiments in P2Y12-deficient mice.[4] Excessive neuronal glutamate release associated with neurodegenerative processes serves as a signal for differential activation of microglia, presumably through activation of different glutamate receptors, in particular α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and metabotropic glutamate receptors, as shown by chemotactic experiments in cell culture and spinal cord slices where green fluorescent protein (GFP) -expressing microglia could be seen to respond to concentration gradients of glutamate.[5] Chemokines released by endangered neurons, in particular CX3CL1 and CCL21, may also act as chemoattractants for microglia that up-regulate their constitutive expression of the relevant chemokine receptors under pathological https://www.selleckchem.com/products/rxdx-106-cep-40783.html conditions. A role for

CX3CL1–CX3CR1 interaction in microglial migration was first demonstrated in vitro by Harrison et al.,[6] and recently confirmed by ex vivo studies which showed that ablation of CX3CR1 signalling in transgenic CX3CR1GFP/GFP CX3CR1−/− mice did not abrogate dynamic motility of retinal microglia processes, but significantly reduced their rates of movement and microglial migration to laser-induced focal injury.[7] Similar studies have also demonstrated the importance Thalidomide of CCL21–CXCR3

signalling in microglia migration.[8] Microglial activation is not an ‘all-or-none’ process; rather, activated microglia can have different functional states. They can shift from a functional state, mainly associated with the maintenance of CNS homeostasis and plasticity characterized by neuroprotective features, to a pro-inflammatory state often related to defence functions that may occur upon infections, or acute and chronic CNS injuries. In the latter case, ‘classical’ activation of microglia may lead to bystander damage of the CNS resulting in neurotoxicity. In general, the ‘classically activated’ status is associated with production of reactive oxygen species, through increased NADPH oxidase activity, and of pro-inflammatory cytokines, in particular tumour necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and with an increased level of inducible nitric oxide synthase expression.

1b, upper panel), which is corroborated by nitric oxide (NO) production by these two different parasites (Fig. 1b, lower panel). Next, we tested the LPG expression profiles on these two parasites. It was observed that the virulent strain had far higher LPG expression levels than that expressed by the less virulent strain of L. major (Fig. 1c). Because LPG works through TLR-2, this observation suggests that TLR-2 stimulation helps the parasite to survive. To examine this plausible role of TLR-2 we pretreated macrophages with PGN, a TLR-2 ligand, at different time-points, followed by infection with the virulent or less virulent strain. It was observed that PGN prolonged the

survival of the less virulent strain of the L. major parasite (Fig. 1d). These results show that the highly virulent L. major parasite had far higher levels of LPG expression than the less virulent L. major, that LPG helps parasite LDK378 clinical trial survival, and that TLR-2 may play a role in parasite survival. Because TLR-9 deficiency promotes L. major infection, albeit transiently

[10], as does LPG [2], which is reported to interact with TLR-2 [5], we tested whether or not these two strains of L. major differ in their capacity to inhibit TLR-9 expression in macrophages. It was observed that 5ASKH/LP, but not 5ASKH/HP, inhibited TLR-9 expression in BALB/c-derived thioglycolate-elicited peritoneal macrophages (Fig. 2a,b). Corroborating this observation, anti-TLR-2 antibody or anti-LPG antibody prevented the 5ASKH/LP-induced down-regulation of TLR-9 expression selleck kinase inhibitor in macrophages (Fig. 2,d). In addition other TLR-2 ligands, Pam3CSK4 and PGN, inhibited Megestrol Acetate TLR-9 expression whereas the TLR-4 ligand, LPS, or the TLR-5 ligand, flagellin, did not impair TLR-9 expression

(Fig. 2e). These observations suggest that LPG down-regulates TLR-9 expression possibly by interacting through TLR-2. Next, we examined the mechanism of LPG-induced suppression of TLR-9 expression in macrophages. As TGF-β and IL-10 are found to promote L. major infection [14, 15], albeit through different mechanisms [16], we examined if LPG induced these two cytokines. It was observed that in BALB/c-derived thioglycolate-elicited macrophages, LPG induced the expression of TGF-β (Fig. 2f, left and middle panel) and IL-10 (Fig. 2f, extreme right panel), both of which suppressed TLR-9 expression in a dose-dependent manner (Fig. 2g). All these observations suggest, for the first time, that LPG plays a significant role in inhibiting TLR-9 expression in macrophages and that TLR-2 plays a significant role in inhibiting TLR-9 expression. Because TLR-9 is reported to promote a host-protective immune response, but LPG is observed to suppress TLR-9 expression, we tested whether antibodies against TLR-2 or LPG would reduce L. major infection of BALB/c-derived peritoneal macrophages. It was observed that both anti-TLR-2 and anti-LPG antibodies reduced L. major infection significantly in macrophages (Fig.

A natural hypothesis given these findings Trichostatin A is that the diminished exhaustion seen in LTNPs could be dependent on lower expression of Blimp-1. This is the possibility addressed in the paper published in this issue of the European Journal of Immunology, in which Seddiki et al. [18] present experiments measuring Blimp-1 levels in the CD4+ T cells from HIV+ LTNPs, individuals with CHI and healthy controls. These experiments showed that, at both the protein and mRNA levels, Blimp-1 expression is higher in individuals with CHI than in LTNPs. Supporting this was the finding

that the downstream effects of elevated Blimp-1 expression in chronic infection, namely elevated PD-1 and diminished IL-2 expression, were also more pronounced in individuals with CHI relative to levels in LTNPs. This prompted Seddiki et al. [18] Lumacaftor ic50 to consider the mechanism by which Blimp-1 expression is regulated in T lymphocytes.

One manner in which gene expression is regulated in cells is via microRNA (miR). These are small noncoding sequences of RNA that bind to untranslated regions of target mRNA and either suppress their translation or accelerate their degradation. The authors assessed the ability of different miRs to suppress Blimp-1 expression. In results consistent with those of other researchers [19], Seddiki et al. [18] found that transfection of miR-9 decreased Blimp-1, while increasing IL-2, expression in CD4+ T cells. The authors also demonstrated that, in CD4+ T cells, TCR stimulation leads to expression of miR-9. Finally, to support the hypothesis that diminished Blimp-1 levels in LTNPs is due to miR-9 expression, the authors measured CD4+ T cell miR-9 levels and found them to be elevated in LTNPs relative to levels

in individuals Sorafenib with CHI. This study [18] provides strong evidence that differences in the CD4+ T-cell expression of Blimp-1 can explain the improved anti-viral profile of the CD4+ T cells from LTNPs versus those from individuals with CHI. It supports data gained from the murine system and proposes, together with another recent publication [19], a novel mechanism for Blimp-1 regulation. The therapeutic possibility raised by this work is that a reduction of Blimp-1 levels in individuals with CHI could improve viral control and provide the proof that the improved viral control seen in LTNPs is Blimp-1 dependent. That this is an important consideration in T-cell directed therapies for HIV is underlined by the failure of IL-2 therapy in HIV to produce a clinical benefit despite improving the CD4+ T-cell count [20]. Blimp-1 was initially described as being dependent on IL-2 signalling and the failure of IL-2 therapy may therefore be attributable to the IL-2-induced Blimp-1 expression and the exhausted phenotype that it promotes.