PAR2 Promotes Vaccine-Induced Protection Against Helicobacter Infection in Mice.

BACKGROUND & AIMS: Protective immunization limits Helicobacter infection of mice by undetermined mechanisms. Protease-activated receptor 2 (PAR2) signaling is believed to regulate immune and inflammatory responses. We investigated the role of PAR2 in vaccine-induced immunity against Helicobacter infection. METHODS: Immune responses against Helicobacter infection were compared between vaccinated PAR2(-/-) and wild-type (WT) mice. Bacterial persistence, gastric pathology, and inflammatory and cellular responses were assessed using the rapid urease test (RUT), histologic analyses, quantitative polymerase chain reaction, and flow cytometry, respectively. RESULTS: Following vaccination, PAR2(-/-) mice did not have reductions in Helicobacter felis infection (RUT values were 0.01 ± 0.01 for WT mice and 0.11 ± 0.13 for PAR2(-/-) mice; P < .05). The vaccinated PAR2(-/-) mice had reduced inflammation-induced stomach tissue damage (tissue damage scores were 8.83 ± 1.47 for WT mice and 4.86 ± 1.35 for PAR2(-/-) mice; P < .002) and reduced T-helper (Th)17 responses, based on reduced urease-induced interleukin (IL)-17 secretion by stomach mononuclear cells (5182 ± 1265 pg/mL for WT mice and 350 ± 436 pg/mL for PAR2(-/-) mice; P < .03) and reduced recruitment of CD4(+) IL-17(+) T cells into the gastric mucosa of PAR2(-/-) mice following bacterial challenge (3.7% ± 1.5% for WT mice and 2.6% ± 1.1% for PAR2(-/-) mice; P < .05). In vitro, H felis-stimulated dendritic cells (DCs) from WT mice induced greater secretion of IL-17 by ovalbumin-stimulated OT-II transgenic CD4(+) T cells compared with DCs from PAR2(-/-) mice (4298 ± 347 and 3230 ± 779; P < .04), indicating that PAR2(-/-) DCs are impaired in priming of Th17 cells. Adoptive transfer of PAR2(+/+) DCs into vaccinated PAR2(-/-) mice increased vaccine-induced protection (RUT values were 0.11 ± 0.10 and 0.26 ± 0.15 for injected and noninjected mice, respectively; P < .03). CONCLUSIONS: PAR2 activates DCs to mediate vaccine-induced protection against Helicobacter infection in mice.

ROLES OF ACID-SENSING ION CHANNELS (ASICS) IN PERIPHERAL NEUROPEPTIDE SECRETION AND PAIN

Acid-sensing ion channels (ASICs) are non-voltage-gated sodium channels activated by an extracellular acidification. They are widely expressed in neurons of the central and peripheral nervous system. ASICs have a role in learning, the expression of fear, in neuronal death after cerebral ischemia, and in pain sensation. Tissue damage leads to the release of inflammatory mediators. There is a subpopulation of sensory neurons which are able to release the neuropeptides calcitonin gene-related peptide (CGRP) and substance P (SP). Neurogenic inflammation refers to the process whereby peripheral release of the neuropeptides CGRP and SP induces vasodilation and extravasation of plasma proteins, respectively. Our laboratory has previously shown that calcium-permeable homomeric ASIC1a channels are present in a majority of CGRP- or SP-expressing small diameter sensory neurons. In the first part of my thesis, we tested the hypothesis that a local acidification can produce an ASIC-mediated calcium-dependant neuropeptide secretion. We have first verified the co-expression of ASICs and CGRP/SP using immunochemistry and in-situ hybridization on dissociated rat dorsal root ganglion (DRG) neurons. We found that most CGRP/SP-positive neurons also expressed ASIC1a and ASIC3 subunits. Calcium imaging experiments with Fura-2 dye showed that an extracellular acidification can induce an increase of intracellular Ca2+ concentration, which is essential for secretion. This increase of intracellular Ca2+ concentration is, at least in some cells, ASIC-dependent, as it can be prevented by amiloride, an ASIC antagonist, and by Psalmotoxin (PcTx1), a specific ASIC1a antagonist. We identified a sub-population of neurons whose acid-induced Ca2+ entry was completely abolished by amiloride, an amiloride-resistant population which does not express ASICs, but rather another acid-sensing channel, possibly transient receptor potential vanilloïde 1 (TRPV1), and a population expressing both H+-gated channel types. Voltage-gated calcium channels (Cavs) may also mediate Ca2+ entry. Co-application of the Cavs inhibitors (ω-conotoxin MVIIC, Mibefradil and Nifedipine) reduced the Ca2+ increase in neurons expressing ASICs during an acidification to pH 6. This indicates that ASICs can depolarise the neuron and activate Cavs. Homomeric ASIC1a are Ca2+-permeable and allow a direct entry of Ca2+ into the cell; other ASICs mediate an indirect entry of Ca2+ by inducing a membrane depolarisation that activates Cavs. We showed with a secretion assay that CGRP secretion can be induced by extracellular acidification in cultured rat DRG neurons. Amiloride and PcTx1 were not able to inhibit the secretion at acidic pH, but BCTC, a TRPV1 inhibitor was able to decrease the secretion induced by an extracellular acidification in our in vitro secretion assay. In conclusion, these results show that in DRG neurons a mild extracellular acidification can induce a calcium-dependent neuropeptide secretion. Even if our data show that ASICs can mediate an increase of intracellular Ca2+ concentration, this appears not to be sufficient to trigger neuropeptide secretion. TRPV1, a calcium channel whose activation induces a sustained current - in contrary of ASICs - played in our experimental conditions a predominant role in neurosecretion. In the second part of my thesis, we focused on the role of ASICs in neuropathic pain. We used the spared nerve injury (SNI) model which consists in a nerve injury that induces symptoms of neuropathic pain such as mechanical allodynia. We have previously shown that the SNI model modifies ASIC currents in dissociated rat DRG neurons. We hypothesized that ASICs could play a role in the development of mechanical allodynia. The SNI model was performed on ASIC1a, -2, and -3 knock-out mice and wild type littermates. We measured mechanical allodynia on these mice with calibrated von Frey filaments. There were no differences between the wild-type and the ASIC1, or ASIC2 knockout mice. ASIC3 null mice were less sensitive than wild type mice at 21 day after SNI, indicating a role for ASIC3. Finally, to investigate other possible roles of ASICs in the perception of the environment, we measured the baseline heat responses. We used two different models; the tail flick model and the hot plate model. ASIC1a null mice showed increased thermal allodynia behaviour in the hot plate test at three different temperatures (49, 52, 55°C) compared to their wild type littermates. On the contrary, ASIC2 null mice showed reduced thermal allodynia behaviour in the hot plate test compared to their wild type littermates at the three same temperatures. We conclude that ASIC1a and ASIC2 in mice can play a role in temperature sensing. It is currently not understood how ASICs are involved in temperature sensing and what the reason for the opposed effects in the two knockout models is.

The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response.

The innate immune system recognizes nucleic acids during infection and tissue damage. Whereas viral RNA is detected by endosomal toll-like receptors (TLR3, TLR7, TLR8) and cytoplasmic RIG-I and MDA5, endosomal TLR9 and cytoplasmic DAI bind DNA, resulting in the activation of nuclear factor-kappaB and interferon regulatory factor transcription factors. However, viruses also trigger pro-inflammatory responses, which remain poorly defined. Here we show that internalized adenoviral DNA induces maturation of pro-interleukin-1beta in macrophages, which is dependent on NALP3 and ASC, components of the innate cytosolic molecular complex termed the inflammasome. Correspondingly, NALP3- and ASC-deficient mice display reduced innate inflammatory responses to adenovirus particles. Inflammasome activation also occurs as a result of transfected cytosolic bacterial, viral and mammalian (host) DNA, but in this case sensing is dependent on ASC but not NALP3. The DNA-sensing pro-inflammatory pathway functions independently of TLRs and interferon regulatory factors. Thus, in addition to viral and bacterial components or danger signals in general, inflammasomes sense potentially dangerous cytoplasmic DNA, strengthening their central role in innate immunity.

Two Cases of Interferon-Alpha-Induced Sarcoidosis Koebnerized along Venous Drainage Lines: New Pathogenic Insights and Review of the Literature of Interferon-Induced Sarcoidosis.

Sarcoidosis is a systemic granulomatous disorder of unknown origin commonly affecting the lung, the lymphoid system and the skin. We report here two cases of cutaneous sarcoidosis in two former intravenous drug users following interferon (IFN)-α and ribavirin therapy for chronic hepatitis C. Both patients developed skin sarcoidosis along venous drainage lines of both forearms, coinciding with the areas of prior drug injections. The unique distribution of the skin lesions suggests that tissue damage induced by repeated percutaneous drug injections represents a trigger for the local skin manifestation of sarcoidosis. Interestingly, skin damage was recently found to induce the local expression IFN-α, a well-known trigger of sarcoidosis in predisposed individuals. Here we review the literature on sarcoidosis elicited in the context of IFN-α therapy and propose a new link between the endogenous expression of IFN-α and the induction of disease manifestations in injured skin. © 2013 S. Karger AG, Basel.

Prothèse totale de la hanche par voie antérieure "mini-invasive" [Total hip arthroplasty through anterior "minimal invasive" approach].

Total hip replacement has seen a tremendous development and has become one of the most successful surgical interventions in orthopaedics. While during the first decades of development of total hip arthroplasty the fixation of the implant into the bone was the main concern, the focus has shifted towards surgical technique and soft tissue handling. In order to avoid permanent soft tissue damage, muscular dysfunction and concerns in regards to cosmetics, minimal invasive and anatomic approaches have been developed. We here provide a short overview on various methods of total hip replacements and we describe our technique through a minimal invasive direct anterior approach. While muscle and nerve damage is minimal, this technique allows for a rapid rehabilitation and is associated with an excellent functional outcome and a minimal risk for dislocation.

Aberrant repair and fibrosis development in skeletal muscle

The repair process of damaged tissue involves the coordinated activities of several cell types in response to local and systemic signals. Following acute tissue injury, infiltrating inflammatory cells and resident stem cells orchestrate their activities to restore tissue homeostasis. However, during chronic tissue damage, such as in muscular dystrophies, the inflammatory-cell infiltration and fibroblast activation persists, while the reparative capacity of stem cells (satellite cells) is attenuated. Abnormal dystrophic muscle repair and its end stage, fibrosis, represent the final common pathway of virtually all chronic neurodegenerative muscular diseases. As our understanding of the pathogenesis of muscle fibrosis has progressed, it has become evident that the muscle provides a useful model for the regulation of tissue repair by the local microenvironment, showing interplay among muscle-specific stem cells, inflammatory cells, fibroblasts and extracellular matrix components of the mammalian wound-healing response. This article reviews the emerging findings of the mechanisms that underlie normal versus aberrant muscle-tissue repair.

Understanding the multifaceted role of inflammatory mediators in ischemic stroke.

The evolution of ischemic brain damage is strongly affected by an inflammatory reaction that involves soluble mediators, such as cytokines and chemokines, and specialized cells activated locally or recruited from the periphery. The immune system affects all phases of the ischemic cascade, from the acute intravascular reaction due to blood flow disruption, to the development of brain tissue damage, repair and regeneration. Increased endothelial expression of adhesion molecules and blood-brain barrier breakdown promotes extravasation and brain recruitment of blood-borne cells, including macrophages, neutrophils, dendritic cells and T lymphocytes, as demonstrated both in animal models and in human stroke. Nevertheless, most anti-inflammatory approaches showing promising results in experimental stroke models failed in the clinical setting. The lack of translation may reside in the redundancy of most inflammatory mediators, exerting both detrimental and beneficial functions. Thus, this review is aimed at providing a better understanding of the dualistic role played by each component of the inflammatory/immune response in relation to the spatio-temporal evolution of ischemic stroke injury.

Sustained NKG2D engagement induces cross-tolerance of multiple distinct NK cell activation pathways

NKG2D is a multisubunit activation receptor that allows natural killer (NK) cells to detect and eliminate stressed, infected, and transformed host cells. However, the chronic exposure of NK cells to cell-bound NKG2D ligands has been shown to impair NKG2D function both in vitro and in vivo. Here we have tested whether continuous NKG2D engagement selectively impacted NKG2D function or whether heterologous NK cell activation pathways were also affected. We found that sustained NKG2D engagement induced cross-tolerization of several unrelated NK cell activation receptors. We show that receptors that activate NK cells via the DAP12/KARAP and DAP10 signaling adaptors, such as murine NKG2D and Ly49D, cross-tolerize preferentially NK cell activation pathways that function independent of DAP10/12, such as antibody-dependent cell-mediated cytotoxicity and missing-self recognition. Conversely, DAP10/12-independent pathways are unable to cross-tolerize unrelated NK cell activation receptors such as NKG2D or Ly49D. These data define a class of NK cell activation receptors that can tolerize mature NK cells. The reversible suppression of the NK cells' cytolytic function probably reduces the NK cells' efficacy to control endogenous and exogenous stress yet may be needed to limit tissue damage

Les fractures du pilon tibial. Etude rétrospective à long terme de 51 fractures traitées par réduction sanglante et ostéosynthèse [Fractures of the tibial pilon. Long-term retrospective study of 51 fractures treated with open reduction and osteosynthesis].

PURPOSE OF THE STUDY: Fracture of the tibial pilon is a rare injury and its treatment remains difficult. The aim of this study was to report the complications and long term results of internal fixation using a technique which respects soft tissues and in which little material was used. MATERIAL: From 1985 to 1990, 48 patients with 51 fractures of the tibial pilon were treated by open reduction and internal fixation. All patients were submitted to a clinical and radiological review. METHODS: Both the Rüedi/Allgöwer and the AO-classification were used and determined by standard X-rays. Surgical procedure was performed with a 2 or 3 1/3 tube AO-plates and the peroneus was always fixed if fractured. Intraoperative reconstruction was analyzed. Subjective and objective scoring were used according to Olerud and Molander and the ankle arthritis was scored according to the classification determined by the SOFCOT in 1992. RESULTS: A minimal follow-up of 1 year for all cases was obtained, based on our own files. Thirty-eight patients (40 fractures) were evaluated after an average period of 88 months (56 to 124 months). Five patients developed cutaneous infection, three developed deep infection and four developed superficial skin necrosis. One aseptic non-union necessitated reoperation after 14 months. Two ankles had joint fusion after 19 and 25 months respectively due to severe arthritis. In six cases infectious and non-infectious complications led to surgical revision. According to the Olerud and Molander score, 15 per cent of the results were excellent, 45 per cent were good, 30 per cent were fair and 10 per cent poor. DISCUSSION: Literature shows a wide range of results following this surgical procedure. This is due to the difference in the type of trauma, classification system used, material used for the internal fixation and method of evaluation. The classification system of Rüedi and Allgöwer is the most commonly used but has a rather subjective tendency, especially between type II and type III. Treatment is difficult, especially for comminutive fractures associated with soft tissue damage. In this case, open reduction and internal fixation could increase iatrogenic lesions. For this reason surgical procedure can be delayed for several days, little material is used and soft tissue manipulation is reduced to minimum. In other study reports, the use of external fixation with or without minimal internal fixation have produced less complications without improving long term results. CONCLUSION: Analysis and comparison of study reports are difficult because of the absence of consensus in classification system and evaluation methods. The AO-classification, apparently the most objective, will probably be more and more used in the future. Treatment must be adapted to the bony lesion and soft tissue damage. Open reduction and internal fixation must be reserved for a specific group of lesion.

Intraoperative photodynamic therapy of the chest cavity in malignant pleural mesothelioma bearing rats.

BACKGROUND AND OBJECTIVE: Experimental assessment of anticancer effect, normal tissue damage, and toxicity of intrathoracic mTHPC-mediated photodynamic therapy (PDT) combined to surgery in malignant pleural mesothelioma (MPM) bearing rats. STUDY DESIGN/MATERIALS AND METHODS: Six days after implantation of syngenic malignant mesothelioma cells in the left chest cavity of Fischer rats (n = 21) and 4 days after sensitization (0.1 mg/kg mTHPC), a left-sided pneumonectomy was performed, followed by intraoperative light delivery (652 nm, fluence 20 J/cm(2)), either by spherical illumination of the chest cavity (fluence rate 15 mW/cm(2)) or by focal illumination of a tumor area (fluence rate 150 mW/cm(2)). Controls comprised tumor-bearing untreated animals, tumor-bearing animals undergoing pneumonectomy, and tumor-bearing animals undergoing pneumonectomy and light delivery without sensitization or sensitization without light delivery. No thoracocentesis was performed during follow-up. RESULTS: An invasively growing sarcomatous type of mesothelioma was found in all animals at day 10, without tumor necrosis in control animals. PDT resulted in 0.5-1 mm deep inhomogeneous tumor necrosis after spherical, and in a 1-2 mm deep tumor necrosis after focal illumination. No injury to mediastinal organs was observed, neither after PDT with spherical nor with focal light delivery except focal interstitial lung fibrosis at the mediastinal area of the opposite lung. All animals with pneumonectomy followed by spherical PDT of the entire tumor-bearing chest cavity died within 72 hours whereas all other animals survived. All animals that died presented massive pleural effusion. CONCLUSIONS: PDT following pneumonectomy in mesothelioma bearing rats was technically feasible and allowed to study its effect on tumor and normal tissues. PDT-related tumor necrosis was observed after spherical and focal light delivery, however, pneumonectomy followed by PDT with spherical light delivery to the tumor-bearing chest cavity resulted in fatal complications.

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

Chronic viral infections and malignant tumours induce T cells that have a reduced ability to secrete effector cytokines and have upregulated expression of the inhibitory receptor PD1 (programmed cell death protein 1). These features have so far been considered to mark terminally differentiated 'exhausted' T cells. However, several recent clinical and experimental observations indicate that phenotypically exhausted T cells can still mediate a crucial level of pathogen or tumour control. In this Opinion article, we propose that the exhausted phenotype results from a differentiation process in which T cells stably adjust their effector capacity to the needs of chronic infection. We argue that this phenotype is optimized to cause minimal tissue damage while still mediating a critical level of pathogen control. In contrast to the presently held view of functional exhaustion, this new concept better reflects the pathophysiology and clinical manifestations of persisting infections, and it provides a rationale for emerging therapies that enhance T cell activity in chronic infection and cancer by blocking inhibitory receptors.

Kinetics of selective oxidation of lactose to lactobionic acid over Pd-active carbon catalyst

Laktoosi eli maitosokeri on tärkein ainesosa useimpien nisäkkäiden tuottamassa maidossa. Sitä erotetaan herasta, juustosta ja maidosta. Laktoosia käytetään elintarvike- ja lääketeollisuuden raaka-aineena monissaeri tuotteissa. Lääketeollisuudessa laktoosia käytetään esimerkiksi tablettien täyteaineena. Hapettamalla laktoosia voidaan valmistaa laktobionihappoa, 2-keto-laktobionihappoa ja laktuloosia. Laktobionihappoa käytetään biohajoavien pintojen ja kosmetiikkatuotteiden valmistuksessa, sekä sisäelinten säilöntäliuoksissa, joissa laktobionihappo estää happiradikaalien aiheuttamien kudosvaurioiden syntymistä. Tässä työssä laktoosia hapetettiin laktobionihapoksi sekoittimella varustetussa laboratoriomittakaavaisessa panosreaktorissa käyttäenkatalyyttinä palladiumia aktiivihiilellä. Muutamissa kokeissa katalyytin promoottorina käytettiin vismuttia, joka hidastaa katalyytin deaktivoitumista. Työn tarkoituksena oli saada lisää tietoa laktoosin hapettamisen kinetiikasta. Laktoosin hapettumisessa laktobionihapoksi havaittiin selektiivisyyteen vaikuttavan muunmuassa reaktiolämpötila, paine, pH ja käytetyn katalyytin määrä. Katalyyttiä kierrättämällä eri kokeiden välillä saatiin paremmat konversiot, selektiivisyydet ja saannot. Parhaat koetulokset saatiin hapetettaessa synteettisellä ilmalla 60 oC lämpötilassa ja 1 bar paineessa. Tehdyissä kokeissa pH:n säätö tehtiin manuaalisesti, joten pH ei pysynyt koko ajan haluttuna. Laktoosin konversio oli parhaimmillaan 95 %. Laktobionihapon suhteellinen selektiivisyys oli 100% ja suhteellinen saanto 100 %. Kinetiikan matemaattinen mallinnus tehtiin Modest-ohjelmalla käyttäen kokeista saatuja mittaustuloksia.Ohjelman avulla estimoitiin parametreja ja saatiin matemaattinen malli reaktorille. Tässä työssä tehtiin kineettinen mallinnus myös ravistelureaktorissa tehdyille laktoosin hapetuskokeille, missä pH pysyi koko ajan haluttuna 'in-situ' titrauksen avulla. Työn yhteydessä selvitettiin myös mahdollisuutta käyttää monoliittikatalyyttejä laktoosin hapetusreaktiossa.

New evidence of neuroprotection by lactate after transient focal cerebral ischaemia: extended benefit after intracerebroventricular injection and efficacy of intravenous administration.

BACKGROUND: Lactate protects mice against the ischaemic damage resulting from transient middle cerebral artery occlusion (MCAO) when administered intracerebroventricularly at reperfusion, yielding smaller lesion sizes and a better neurological outcome 48 h after ischaemia. We have now tested whether the beneficial effect of lactate is long-lasting and if lactate can be administered intravenously. METHODS: Male ICR-CD1 mice were subjected to 15-min suture MCAO under xylazine + ketamine anaesthesia. Na L-lactate (2 µl of 100 mmol/l) or vehicle was administered intracerebroventricularly at reperfusion. The neurological deficit was evaluated using a composite deficit score based on the neurological score, the rotarod test and the beam walking test. Mice were sacrificed at 14 days. In a second set of experiments, Na L-lactate (1 µmol/g body weight) was administered intravenously into the tail vein at reperfusion. The neurological deficit and the lesion volume were measured at 48 h. RESULTS: Intracerebroventricularly injected lactate induced sustained neuroprotection shown by smaller neurological deficits at 7 days (median = 0, min = 0, max = 3, n = 7 vs. median = 2, min = 1, max = 4.5, n = 5, p < 0.05) and 14 days after ischaemia (median = 0, min = 0, max = 3, n = 7 vs. median = 3, min = 0.5, max = 3, n = 7, p = 0.05). Reduced tissue damage was demonstrated by attenuated hemispheric atrophy at 14 days (1.3 ± 4.0 mm(3), n = 7 vs. 12.1 ± 3.8 mm(3), n = 5, p < 0.05) in lactate-treated animals. Systemic intravenous lactate administration was also neuroprotective and attenuated the deficit (median = 1, min = 0, max = 2.5, n = 12) compared to vehicle treatment (median = 1.5, min = 1, max = 8, n = 12, p < 0.05) as well as the lesion volume at 48 h (13.7 ± 12.2 mm(3), n = 12 vs. 29.6 ± 25.4 mm(3), n = 12, p < 0.05). CONCLUSIONS: The beneficial effect of lactate is long-lasting: lactate protects the mouse brain against ischaemic damage when supplied intracerebroventricularly during reperfusion with behavioural and histological benefits persisting 2 weeks after ischaemia. Importantly, lactate also protects after systemic intravenous administration, a more suitable route of administration in a clinical emergency setting. These findings provide further steps to bring this physiological, commonly available and inexpensive neuroprotectant closer to clinical translation for stroke.

Xanthine oxidoreductase regulates macrophage IL1β secretion upon NLRP3 inflammasome activation.

Activation of the NLRP3 inflammasome by microbial ligands or tissue damage requires intracellular generation of reactive oxygen species (ROS). We present evidence that macrophage secretion of IL1β upon stimulation with ATP, crystals or LPS is mediated by a rapid increase in the activity of xanthine oxidase (XO), the oxidized form of xanthine dehydrogenase, resulting in the formation of uric acid as well as ROS. We show that XO-derived ROS, but not uric acid, is the trigger for IL1β release and that XO blockade results in impaired IL1β and caspase1 secretion. XO is localized to both cytoplasmic and mitochondrial compartments and acts upstream to the PI3K-AKT signalling pathway that results in mitochondrial ROS generation. This pathway represents a mechanism for regulating NLRP3 inflammasome activation that may have therapeutic implications in inflammatory diseases.

Inhibitory Receptors Beyond T Cell Exhaustion.

Inhibitory receptors (iRs) are frequently associated with "T cell exhaustion". However, the expression of iRs is also dependent on T cell differentiation and activation. Therapeutic blockade of various iRs, also referred to as "checkpoint blockade", is showing -unprecedented results in the treatment of cancer patients. Consequently, the clinical potential in this field is broad, calling for increased research efforts and rapid refinements in the understanding of iR function. In this review, we provide an overview on the significance of iR expression for the interpretation of T cell functionality. We summarize how iRs have been strongly associated with "T cell exhaustion" and illustrate the parallel evidence on the importance of T cell differentiation and activation for the expression of iRs. The differentiation subsets of CD8 T cells (naïve, effector, and memory cells) show broad and inherent differences in iR expression, while activation leads to strong upregulation of iRs. Therefore, changes in iR expression during an immune response are often concomitant with T cell differentiation and activation. Sustained expression of iRs in chronic infection and in the tumor microenvironment likely reflects a specialized T cell differentiation. In these situations of prolonged antigen exposure and chronic inflammation, T cells are "downtuned" in order to limit tissue damage. Furthermore, we review the novel "checkpoint blockade" treatments and the potential of iRs as biomarkers. Finally, we provide recommendations for the immune monitoring of patients to interpret iR expression data combined with parameters of activation and differentiation of T cells.