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1.
Cancer ; 126(15): 3438-3447, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32459375

RESUMO

BACKGROUND: Long-term treatment-free remission (TFR) represents a new goal for chronic myeloid leukemia (CML). In clinical practice, tyrosine kinase inhibitor (TKI) dose reductions can be considered a means of preventing adverse effects and improving quality of life. We hypothesized that administration of low-dose TKIs before treatment discontinuation does not impair TFR in patients with CML who have a deep molecular response (DMR, ≥MR4 ). METHODS: We conducted a retrospective analysis of 77 patients with CML who discontinued treatment with TKIs. Twenty-six patients had been managed with low-dose TKIs before stopping treatment. Patients were to be exposed to TKIs for ≥5 years and to low-dose TKIs for ≥1 year and in DMR for ≥2 years. The loss of major molecular response (MMR) was considered a trigger for restarting therapy. RESULTS: In the low-dose group, 61.5% of patients received second-generation TKIs, and dose reduction was ≥50% for 65.4% of patients. With a median follow-up of 61.5 months, TFR at 12 months was 56.8% in the full-dose TKI group and 80.8% in the low-dose group, and TFR at 60 months was 47.5% and 58.8%, respectively. The median time to molecular recurrence (≥MMR) from TKI discontinuation in the entire cohort was 6.2 months. All patients quickly achieved MMR after resuming TKI therapy. Results appear independent of both dose reduction and potential pretreatment with interferon-α. CONCLUSION: This retrospective study shows that TFR was not impaired by low-dose TKI regimens before TKI cessation in Patients with CML. Nevertheless, prospective randomized clinical trials must be undertaken to analyze the probability of successful TFR in patients managed with TKI dose de-escalation strategies before TKI discontinuation.


Assuntos
Relação Dose-Resposta a Droga , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Indução de Remissão , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/epidemiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
2.
Br J Haematol ; 186(1): 54-59, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30864168

RESUMO

Immunological mechanisms of treatment-free remission (TFR) in chronic myeloid leukaemia (CML) are poorly defined and, to date, no correlation between successful TFR and CD8(+) T-cell subsets has been found. We analysed a new identified human subset of CD8(+) T-cells, namely innate CD8(+) T-cells, in CML patients with TFR ≥ 2 years. We demonstrated a dramatic increase of functionally active innate CD8(+) T-cells in these patients as compared to control subjects and patients in remission under tyrosine kinase inhibitors. Moreover, we found a positive correlation between frequencies of innate CD8(+) T-cells and natural killer cells, possibly representing a new innate biomarker profile of successful TFR.


Assuntos
Linfócitos T CD8-Positivos/patologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Remissão Espontânea , Estudos de Casos e Controles , Feminino , Humanos , Imunidade Inata , Células Matadoras Naturais , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Subpopulações de Linfócitos T/imunologia
3.
J Am Soc Nephrol ; 29(4): 1272-1288, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29436517

RESUMO

Inflammation is a prominent feature of ischemia-reperfusion injury (IRI), which is characterized by leukocyte infiltration and renal tubular injury. However, signals that initiate these events remain poorly understood. We examined the role of the nuclear alarmin IL-33 in tissue injury and innate immune response triggered by experimental kidney ischemia-reperfusion. In wild-type mice, we found that IL-33 was constitutively expressed throughout the kidney in peritubular and periglomerular spaces, mainly by microvascular endothelial cells, from which it was released immediately during IRI. Compared with wild-type mice, mice lacking IL-33 (IL-33Gt/Gt) exhibited reductions in early tubular cell injury and subsequent renal infiltration of IFN-γ/IL-17A-producing neutrophils, with preservation of renal functions. This protection associated with decreased renal recruitment of myeloid dendritic cells, natural killer (NK) cells, and invariant natural killer T (iNKT) cells, the latter of which were reported as deleterious in IRI. Increases in the level of circulating IL-12, a key IL-33 cofactor, and the expression of ST2, an IL-33-specific receptor, on the surface of iNKT cells preceded the IL-33- and iNKT cell-dependent phase of neutrophil infiltration. Furthermore, IL-33 directly targeted iNKT cells in vitro, inducing IFN-γ and IL-17A production. We propose that endogenous IL-33 is released as an alarmin and contributes to kidney IRI by promoting iNKT cell recruitment and cytokine production, resulting in neutrophil infiltration and activation at the injury site. Our findings show a novel molecular mediator contributing to innate immune cell recruitment induced by renal ischemia-reperfusion and may provide therapeutic insights into AKI associated with renal transplantation.


Assuntos
Alarminas/fisiologia , Interleucina-33/fisiologia , Rim/irrigação sanguínea , Traumatismo por Reperfusão/metabolismo , Alarminas/deficiência , Alarminas/genética , Animais , Citocinas/biossíntese , Citocinas/genética , Células Dendríticas/imunologia , Regulação da Expressão Gênica/imunologia , Imunidade Inata , Interferon gama/biossíntese , Interferon gama/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/deficiência , Proteína 1 Semelhante a Receptor de Interleucina-1/fisiologia , Interleucina-12/sangue , Interleucina-17/biossíntese , Interleucina-17/genética , Interleucina-33/biossíntese , Interleucina-33/deficiência , Interleucina-33/genética , Rim/imunologia , Rim/metabolismo , Rim/patologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ativação de Neutrófilo , Neutrófilos/imunologia , Traumatismo por Reperfusão/imunologia
4.
Immunity ; 30(2): 289-99, 2009 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-19217323

RESUMO

Invariant natural killer T (iNKT) cells promote immune responses to various pathogens, but exactly how iNKT cells control antiviral responses is unclear. Here, we showed that iNKT cells induced tissue-specific antiviral effects in mice infected by lymphocytic choriomeningitis virus (LCMV). Indeed, iNKT cells inhibited viral replication in the pancreas and liver but not in the spleen. In the pancreas, iNKT cells expressed the OX40 molecule and promoted type I interferon (IFN) production by plasmacytoid dendritic cells (pDCs) through OX40-OX40 ligand interaction. Subsequently, this iNKT cell-pDC cooperation attenuated the antiviral adaptive immune response in the pancreas but not in the spleen. The dampening of pancreatic anti-LCMV CD8(+) T cell response prevented tissue damage in transgenic mice expressing LCMV protein in islet beta cells. Thus, this study identifies pDCs as an essential partner of iNKT cells for mounting an efficient, nondeleterious antiviral response in peripheral tissue.


Assuntos
Células Dendríticas/imunologia , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/virologia , Vírus da Coriomeningite Linfocítica/imunologia , Células T Matadoras Naturais/imunologia , Receptores OX40/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Diabetes Mellitus/etiologia , Diabetes Mellitus/imunologia , Diabetes Mellitus/virologia , Fígado/imunologia , Fígado/virologia , Coriomeningite Linfocítica/complicações , Camundongos , Ligante OX40/imunologia , Especificidade de Órgãos/imunologia , Pâncreas/imunologia , Pâncreas/virologia , Transdução de Sinais/imunologia , Baço/imunologia , Baço/virologia , Replicação Viral
5.
J Immunol ; 197(5): 1708-19, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27474075

RESUMO

IL-33 is strongly involved in several inflammatory and autoimmune disorders with both pro- and anti-inflammatory properties. However, its contribution to chronic autoimmune inflammation, such as rheumatoid arthritis, is ill defined and probably requires tight regulation. In this study, we aimed at deciphering the complex role of IL-33 in a model of rheumatoid arthritis, namely, collagen-induced arthritis (CIA). We report that repeated injections of IL-33 during induction (early) and during development (late) of CIA strongly suppressed clinical and histological signs of arthritis. In contrast, a late IL-33 injection had no effect. The cellular mechanism involved in protection was related to an enhanced type 2 immune response, including the expansion of eosinophils, Th2 cells, and type 2 innate lymphoid cells, associated with an increase in type 2 cytokine levels in the serum of IL-33-treated mice. Moreover, our work strongly highlights the interplay between IL-33 and regulatory T cells (Tregs), demonstrated by the dramatic in vivo increase in Treg frequencies after IL-33 treatment of CIA. More importantly, Tregs from IL-33-treated mice displayed enhanced capacities to suppress IFN-γ production by effector T cells, suggesting that IL-33 not only favors Treg proliferation but also enhances their immunosuppressive properties. In concordance with these observations, we found that IL-33 induced the emergence of a CD39(high) Treg population in a ST2L-dependent manner. Our findings reveal a powerful anti-inflammatory mechanism by which IL-33 administration inhibits arthritis development.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Interleucina-33/uso terapêutico , Linfócitos T Reguladores/imunologia , Células Th2/imunologia , Animais , Antígenos CD/genética , Apirase/genética , Artrite Experimental , Artrite Reumatoide/induzido quimicamente , Doenças Autoimunes/imunologia , Colágeno/administração & dosagem , Citocinas/sangue , Modelos Animais de Doenças , Eosinófilos , Interleucina-33/imunologia , Interleucina-33/farmacologia , Camundongos , Camundongos Endogâmicos DBA , Baço/citologia , Baço/efeitos dos fármacos
6.
J Pathol ; 240(3): 262-268, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27513300

RESUMO

CD1d-restricted invariant natural killer T (iNKT) cells are believed to play a key role in cancer immune surveillance, and are functionally deficient in patients with chronic myeloid leukaemia (CML). Herein, we have hypothesized that this defect might originate from BCR-ABL-dependent dysfunctions in myeloid dendritic cells (mDCs). Indeed, flow cytometry and confocal microscopy revealed that cell surface expression of CD1d was downregulated in CML mDCs, relative to healthy donor (HD) controls. The decreased cell surface display of CD1d could not be ascribed to defective mDC differentiation, as attested by normal expression of HLA-DR and the CD86 maturation marker. On the other hand, reduced membrane expression was not associated with decreased intracytoplasmic levels of CD1d or its mRNA transcripts, consistent with intracellular retention. In vitro treatment of CML mDCs with the Rho-associated protein kinase (ROCK) inhibitor Y-27632 partially restored both cell surface CD1d expression and CD1d-mediated antigen presentation, whereas it had no effect on HD mDCs. An inhibitor of BCR-ABL tyrosine kinase (TK), imatinib mesylate (IM), had no such activity. Similar recovery of CD1d expression occurred with fasudil, another ROCK inhibitor that is commonly used in clinical trials. Our data support the conclusion that BCR-ABL-dependent ROCK, but not TK, is involved in CD1d downregulation. We propose that ROCK, which is most likely activated by the DH/PH domain of BCR-ABL, mediates iNKT-cell immune subversion in CML patients by downregulating CD1d expression on CML mDCs. Our study reveals the ROCK-mDC axis as a new potential target to restore immune surveillance in patients with CML, offering new therapeutic perspectives for CML treatment. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Antígenos CD1d/imunologia , Imunidade Inata , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Quinases Associadas a rho/imunologia , Amidas/farmacologia , Diferenciação Celular , Células Dendríticas/enzimologia , Células Dendríticas/imunologia , Inibidores Enzimáticos/farmacologia , Proteínas de Fusão bcr-abl/imunologia , Humanos , Mesilato de Imatinib/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/enzimologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Células Mieloides/enzimologia , Células Mieloides/imunologia , Células T Matadoras Naturais/enzimologia , Células T Matadoras Naturais/imunologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Quinases Associadas a rho/antagonistas & inibidores
7.
Eur J Immunol ; 45(7): 1926-33, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25903796

RESUMO

Polyclonal CD8(+) T cells, with a marked innate/memory phenotype, high eomesodermin (Eomes) expression, and the capacity to generate IFN-γ rapidly without prior exposure to antigen, have been described in mice. However, even though a pool of human CD8(+) T cells expressing killer Ig-like receptors (KIRs) was recently documented, the existence of a human equivalent of murine innate/memory CD8(+) T cells remains to be established. Here, we provide evidence for a population of KIR/NKG2A(+) CD8(+) T cells in healthy human adults sharing the same features, namely increased Eomes expression, prompt IFN-γ production in response to innate-like stimulation by IL-12+IL-18, and a potent antigen-independent cytotoxic activity along with a preferential terminally differentiated effector memory phenotype. None of the above functional characteristics applied to the KIR/NKG2A(-) fraction of the Eomes(+) CD8(+) T-cell population, thereby underlining the ability of KIR/NKG2A to distinguish between "innate/memory-like" and "conventional/memory" pools of CD8(+) T cells. Remarkably, KIR/NKG2A(+) Eomes(+) CD8(+) T cells with innate-like functions and a memory/terminally differentiated effector memory phenotype were also identified in human cord blood, suggesting that their development did not depend on cognate antigens. Taken together, our results support the conclusion that CD8(+) T cells co-expressing Eomes and KIR/NKG2A may represent a new, functionally distinct "innate/memory-like" subset in humans.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Imunidade Inata/imunologia , Memória Imunológica/imunologia , Proteínas com Domínio T/imunologia , Subpopulações de Linfócitos T/imunologia , Adulto , Sangue Fetal/citologia , Sangue Fetal/imunologia , Citometria de Fluxo , Humanos , Subfamília C de Receptores Semelhantes a Lectina de Células NK/imunologia
8.
Eur J Immunol ; 42(7): 1870-5, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22585600

RESUMO

Chronic myeloid leukemia (CML) is a clonal hematopoietic stem-cell malignancy characterized by the presence of the chimeric BCR-ABL oncoprotein with deregulated tyrosine-kinase (TK) activity. Although conventional T cells are acknowledged as important players in the control of CML, a possible modification of invariant NKT (iNKT) cells, known for their antitumoral activity, has not been established as yet. Here, we showed that the expression of perforin, CD95L, and promyelocytic leukemia zinc finger, a transcription factor required for maintenance of iNKT cell functions, was reduced or suppressed in CML patients at diagnosis, as compared with healthy individuals. The proliferation rate of blood iNKT cells in response to their cognate ligand was likewise diminished. These functional deficiencies were corrected in patients having achieved complete cytogenetic remission following TK inhibitor or IFN-α therapy. iNKT cells from CML patients in the chronic phase did not display increased TK activity, which argued against a direct autonomous action of BCR-ABL. Instead, we found that their anergic status originated from both intrinsic and APC-dependent dysfunctions. Our data demonstrate that chronic phase CML is associated with functional deficiencies of iNKT cells that are restored upon remission. These results suggest a possible contribution to disease control by TK inhibitor therapies.


Assuntos
Interferon-alfa/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Células T Matadoras Naturais/imunologia , Proteínas Tirosina Quinases/imunologia , Benzamidas , Proteína Ligante Fas/sangue , Citometria de Fluxo , Humanos , Mesilato de Imatinib , Fatores de Transcrição Kruppel-Like/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/enzimologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Células T Matadoras Naturais/enzimologia , Perforina/sangue , Piperazinas/farmacologia , Proteína com Dedos de Zinco da Leucemia Promielocítica , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/farmacologia
9.
Blood ; 118(11): 2993-3002, 2011 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-21653940

RESUMO

Despite increasing knowledge on the mechanisms of invariant natural killer T (iNKT)-cell development in the thymus, the function of recent thymic emigrant (RTE) iNKT cells remains largely unexplored, principally because of a lack of bona fide markers to distinguish RTE from long-lived iNKT cells. Whether the recently described IL-17-producing iNKT cell subset is part of RTE has notably not been addressed. In the present study, we show that neuropilin-1 (Nrp-1), a transmembrane receptor mainly found on T-regulatory (Treg) cells in the murine immune system, is specifically expressed on RTE iNKT cells in naive mice. We used the Nrp-1 marker to discriminate RTE from mature iNKT cells and compare their functions. We show that RTE iNKT cells proliferate more than mature iNKT cells after in vitro activation; that, unlike mature iNKT cells, most RTE iNKT cells fail to rapidly produce IFN-γ and IL-4 after in vivo activation; and, most importantly, that IL-17-producing iNKT cells in lymphoid organs of naive mice are contained within the RTE iNKT cell pool. Our results establish an accurate marker of RTE iNKT cells and reveal that continuous thymic output is required for pro-inflammatory IL-17 secretion, a key function of adult iNKT cells.


Assuntos
Quimiotaxia de Leucócito , Interleucina-17/metabolismo , Tecido Linfoide/imunologia , Células T Matadoras Naturais/metabolismo , Células T Matadoras Naturais/fisiologia , Neuropilina-1/metabolismo , Animais , Separação Celular/métodos , Células Cultivadas , Quimiotaxia de Leucócito/imunologia , Citometria de Fluxo/métodos , Tecido Linfoide/citologia , Tecido Linfoide/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Células T Matadoras Naturais/citologia , Células T Matadoras Naturais/imunologia , Timo/citologia , Timo/imunologia , Timo/metabolismo , Fatores de Tempo
10.
J Immunol ; 186(6): 3289-93, 2011 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-21317388

RESUMO

Despite their increasing use in autoimmune, inflammatory, and allergic conditions, the mechanism of action of i.v. Igs (IVIg) is poorly understood. On the basis of the critical role of invariant NKT (iNKT) cells in allergic airway inflammation (AAI) and their constitutive expression of the low-affinity IgG receptor FcγRIIIA, we surmised that IVIg targets iNKT cells to exert their anti-inflammatory effect. We found that IVIg treatment significantly inhibited AAI in OVA-sensitized C57BL/6 mice and downregulated α-galactosylceramide-induced iNKT cell activation and cytokine production. Allergic responses were restored in iNKT cell-deficient mice by transferring iNKT cells from PBS- but not from IVIg-treated mice, suggesting that IVIg acts directly on activated iNKT cells that have a critical role in AAI. The inhibitory effects of IVIg on both iNKT cell activation/function and OVA-driven AAI were lost in FcγRIIIA(-/-) mice. Our data unravel an FcγRIIIA-dependent inhibitory effect of IVIg on activated iNKT cells that confers protection in AAI.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Imunoglobulinas Intravenosas/fisiologia , Mediadores da Inflamação/fisiologia , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/patologia , Receptores de IgG/fisiologia , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/prevenção & controle , Transferência Adotiva , Alérgenos/imunologia , Alérgenos/toxicidade , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/patologia , Hiper-Reatividade Brônquica/terapia , Citocinas/antagonistas & inibidores , Citocinas/biossíntese , Galactosilceramidas/antagonistas & inibidores , Galactosilceramidas/farmacologia , Imunoglobulinas Intravenosas/uso terapêutico , Mediadores da Inflamação/uso terapêutico , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células T Matadoras Naturais/metabolismo , Ovalbumina/imunologia , Ovalbumina/toxicidade , Receptores de IgG/uso terapêutico , Hipersensibilidade Respiratória/patologia , Baço/imunologia , Baço/patologia , Baço/transplante
11.
J Immunol ; 186(1): 284-90, 2011 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-21131420

RESUMO

It has been documented that TLR7 stimulation triggers not only antiviral responses, but also alleviates experimental asthma. Considering the implication of invariant NKT (iNKT) cells in both situations, we postulated that they might contribute to the anti-inflammatory effect of TLR7 ligands. We show in this study that spleen cells activated by the TLR7 agonist resiquimod (R848) attenuate allergic inflammation upon adoptive transfer when they are recovered from wild-type, but not from iNKT cell-deficient Jα18(-/-) mice, which proves the specific involvement of this regulatory population. Furthermore, we provide evidence that IFN-γ is critical for the protective effect, which is lost when transferred iNKT cells are sorted from IFN-γ-deficient mice. In support of a direct activation of iNKT cells through TLR7 signaling in vivo, we observed a prompt increase of serum IFN-γ levels, associated with upregulation of CD69 expression on iNKT cells. Moreover, we demonstrate that iNKT cells effectively express TLR7 and respond to R848 in vitro by producing high levels of IFN-γ in the presence of IL-12, consistent with the conclusion that their contribution to the alleviation of allergic inflammation upon treatment with TLR7 ligands is mediated through IFN-γ.


Assuntos
Antialérgicos/uso terapêutico , Asma/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Imidazóis/uso terapêutico , Mediadores da Inflamação/uso terapêutico , Interferon gama/biossíntese , Glicoproteínas de Membrana/agonistas , Células T Matadoras Naturais/imunologia , Receptor 7 Toll-Like/agonistas , Transferência Adotiva , Animais , Asma/imunologia , Asma/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células T Matadoras Naturais/efeitos dos fármacos , Células T Matadoras Naturais/transplante , Ovalbumina/administração & dosagem , Ovalbumina/imunologia
12.
Front Immunol ; 14: 1099529, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37228593

RESUMO

Over the past thirty years, the complexity of the αß-T cell compartment has been enriched by the identification of innate-like T cells (ITCs), which are composed mainly of invariant natural killer T (iNKT) cells and mucosal-associated invariant T (MAIT) cells. Based on animal studies using ischemia-reperfusion (IR) models, a key role has been attributed to iNKT cells in close connection with the alarmin/cytokine interleukin (IL)-33, as early sensors of cell-stress in the initiation of acute sterile inflammation. Here we have investigated whether the new concept of a biological axis of circulating iNKT cells and IL-33 applies to humans, and may be extended to other ITC subsets, namely MAIT and γδ-T cells, in the acute sterile inflammation sequence occurring during liver transplant (LT). From a prospective biological collection of recipients, we reported that LT was accompanied by an early and preferential activation of iNKT cells, as attested by almost 40% of cells having acquired the expression of CD69 at the end of LT (i.e. 1-3 hours after portal reperfusion), as opposed to only 3-4% of conventional T cells. Early activation of iNKT cells was positively correlated with the systemic release of the alarmin IL-33 at graft reperfusion. Moreover, in a mouse model of hepatic IR, iNKT cells were activated in the periphery (spleen), and recruited in the liver in WT mice, as early as the first hour after reperfusion, whereas this phenomenon was virtually missing in IL-33-deficient mice. Although to a lesser degree than iNKT cells, MAIT and γδ-T cells also seemed targeted during LT, as attested by 30% and 10% of them acquiring CD69 expression, respectively. Like iNKT cells, and in clear contrast to γδ-T cells, activation of MAIT cells during LT was closely associated with both release of IL-33 immediately after graft reperfusion and severity of liver dysfunction occurring during the first three post-operative days. All in all, this study identifies iNKT and MAIT cells in connection with IL-33 as new key cellular factors and mechanisms of acute sterile inflammation in humans. Further investigations are required to confirm the implication of MAIT and iNKT cell subsets, and to precisely assess their functions, in the clinical course of sterile inflammation accompanying LT.


Assuntos
Hepatopatias , Células T Matadoras Naturais , Animais , Humanos , Camundongos , Alarminas/metabolismo , Inflamação/metabolismo , Interleucina-33/metabolismo , Isquemia/metabolismo , Hepatopatias/metabolismo , Células T Matadoras Naturais/metabolismo , Estudos Prospectivos , Reperfusão
13.
Eur J Immunol ; 41(6): 1720-32, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21469102

RESUMO

Invariant natural killer T (iNKT) cells are involved in the intrahepatic immune response and in hepatitis. In particular, iNKT lymphocytes are responsible for hepatocyte death in concanavalin A-induced hepatitis in mice. We examined the role of iNKT cells in acute hepatitis induced by a hepatotoxic agent, carbon tetrachloride (CCl(4) ). WT and iNKT cell-deficient (Jα18(-/-) ) mice were challenged with a single dose of 2.4 g/kg CCl(4) and both hepatic physiopathology and immune responses were studied. Plasma alanine and aspartate amino-transferase levels were significantly higher in Jα18(-/-) mice than in WT mice two days after CCl(4) administration. Chemokine CXCL1/keratinocyte-derived chemokine (KC) and MMP-8 were significantly higher in iNKT cell-deficient mice than in control mice. The more severe liver injury in Jα18(-/-) mice was associated with greater leukocyte infiltrate, which was enriched in neutrophils (CD11b(+) CD11c(-) Gr-1(+) cells), in agreement with CXCL1/KC and MMP-8 levels. Complementary experiments with NK-depleted animals indicate a minor role for NK cells in the liver damage found in iNKT-deficient mice. Thus, unlike for ConA-induced hepatitis, we report that iNKT cells protect the liver against acute hepatitis induced by CCl(4) and limit neutrophil infiltration.


Assuntos
Quimiocina CXCL1/metabolismo , Hepatite Animal/imunologia , Fígado/metabolismo , Células T Matadoras Naturais/metabolismo , Neutrófilos/metabolismo , Doença Aguda , Alanina/sangue , Animais , Apoptose/efeitos dos fármacos , Aspartato Aminotransferases/sangue , Tetracloreto de Carbono/administração & dosagem , Tetracloreto de Carbono/toxicidade , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Quimiocina CXCL1/genética , Quimiocina CXCL1/imunologia , Hepatite Animal/sangue , Hepatite Animal/induzido quimicamente , Hepatócitos/patologia , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/patologia , Metaloproteinase 8 da Matriz/genética , Metaloproteinase 8 da Matriz/imunologia , Metaloproteinase 8 da Matriz/metabolismo , Camundongos , Camundongos Knockout , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/patologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/patologia , Receptores de Antígenos de Linfócitos T alfa-beta/genética
14.
Eur J Immunol ; 41(2): 299-305, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21268000

RESUMO

Activation of invariant natural killer T (iNKT) cells by treatment with their α-galactosyl ceramide ligand provides therapeutic benefits in several immune inflammatory settings. Given the artificial nature of this stimulation, the natural regulatory functions of iNKT remain uncertain. Addressing this issue in a mouse model of innate-cell-driven lung inflammation induced by the cytokine/alarmin IL-33 that targets iNKT cells, we found that eosinophil and neutrophil recruitment was markedly increased in treated iNKT cell-deficient (Jα18 KO) mice, as was the local production of eotaxin and keratinocyte chemoattractant chemokines. By contrast, lung inflammation decreased after adoptive transfer of iNKT cells, which restored the WT inflammatory response in Jα18 KO mice. Finally, we established that this natural anti-inflammatory function of iNKT cells depends on their IFN-γ production and on endogenous IL-12. Our study provides the first evidence of a protective role of iNKT cells during lung inflammation that does not require pharmacological TCR engagement.


Assuntos
Bronquite/imunologia , Bronquite/patologia , Imunidade Inata/imunologia , Células T Matadoras Naturais/imunologia , Transferência Adotiva , Animais , Bronquite/sangue , Bronquite/induzido quimicamente , Líquido da Lavagem Broncoalveolar/química , Contagem de Células , Quimiocinas/sangue , Quimiocinas/metabolismo , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Eosinófilos/patologia , Feminino , Interferon gama/genética , Interferon gama/metabolismo , Interleucina-12/genética , Interleucina-12/metabolismo , Interleucina-33 , Interleucina-5/sangue , Interleucinas/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Células T Matadoras Naturais/metabolismo , Células T Matadoras Naturais/transplante , Neutrófilos/patologia , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Proteínas Recombinantes/farmacologia
15.
J Immunol ; 184(12): 6585-91, 2010 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-20488793

RESUMO

Administration of attenuated pathogenic T cell clones, a procedure known as T cell vaccination, induces CD8+ T cells specific for peptides derived from the Vbeta-chain of the TCR presented by the MHC class Ib molecule, Qa-1 expressed on the vaccine cells. These regulatory CD8+ T cells have the capacity to control the activation of endogenous T cells expressing the same TCR Vbeta-chain as the vaccinating cells. We hypothesized that vaccination with NKT cells could also induce Qa-1-restricted CD8+ T cells that would control NKT cell activation. We tested this hypothesis in a murine model of Con A-induced hepatitis that is induced by NKT cells. Vaccination with NKT cells effectively induced protective Qa-1-restricted CD8+ T cells that prevented hepatitis. Surprisingly, upon vaccination with T cells expressing Vbeta-chains irrelevant to NKT cells, we discovered that the specificity of vaccine-induced Qa-1-restricted CD8+ T cells was not limited to the Vbeta-chain of the vaccinating cells. We further show that these regulatory Qa-1-restricted CD8+ T cells arise spontaneously upon polyclonal activation of T cells in the absence of deliberate T cell vaccination. These experiments provide new insight into a CD8+ T cell compartment that regulates the immediate reactivation of conventional T cells and NKT cells.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Ativação Linfocitária/imunologia , Células T Matadoras Naturais/imunologia , Subpopulações de Linfócitos T/imunologia , Transferência Adotiva , Animais , Separação Celular , Concanavalina A/imunologia , Concanavalina A/toxicidade , Citometria de Fluxo , Hepatite/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Mitógenos/imunologia , Mitógenos/toxicidade , Células T Matadoras Naturais/transplante , Receptores de Antígenos de Linfócitos T/imunologia , Vacinação
16.
Proc Natl Acad Sci U S A ; 106(15): 6238-43, 2009 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-19325124

RESUMO

T cells differentiate into functionally distinct effector subsets in response to pathogen encounter. Cells of the innate immune system direct this process; CD1d-restricted invariant natural killer T (iNKT) cells, for example, can either promote or inhibit Th(1) and Th(2) responses. Recently, a new subset of CD4(+) T helper cells, called Th(17), was identified that is implicated in mucosal immunity and autoimmune disorders. To investigate the influence of iNKT cells on the differentiation of naïve T cells we used an adoptive transfer model of traceable antigen-specific CD4(+) T cells. Transferred naïve CD25(-)CD62L(+) CD4(+) T cells were primed by antigen immunization of the recipient mice, permitting their expansion and Th(17) differentiation. This study establishes that in vivo activation of iNKT cells during T-cell priming impedes the commitment of naïve T cells to the Th(17) lineage. In vivo cytokine neutralization experiments revealed a role for IL-4, IL-10, and IFN-gamma in the iNKT-cell-mediated regulation of T-cell lineage development. Moreover, by comparing IL-17 production by antigen-experienced T cells from unmanipulated wild-type mice and iNKT-cell-deficient mice, we demonstrate an enhanced Th(17) response in mice lacking iNKT cells. This invigorated Th(17) response reverts to physiological levels when iNKT cells are introduced into Jalpha18(-/-) mice by adoptive transfer, indicating that iNKT cells control the Th(17) compartment at steady state. We conclude that iNKT cells play an important role in limiting development of the Th(17) lineage and suggest that iNKT cells provide a natural barrier against Th(17) responses.


Assuntos
Linhagem da Célula/imunologia , Interleucina-17/imunologia , Células T Matadoras Naturais/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Separação Celular , Células Cultivadas , Encefalomielite Autoimune Experimental/imunologia , Interferon gama/biossíntese , Interferon gama/imunologia , Interleucina-10/biossíntese , Interleucina-10/imunologia , Interleucina-17/biossíntese , Interleucina-4/biossíntese , Interleucina-4/imunologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL
17.
J Interferon Cytokine Res ; 42(12): 624-642, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36083273

RESUMO

The presence of CD8+ T cells with a memory phenotype in nonimmunized mice has been noted for decades, but it was not until about 2 decades ago that they began to be studied in greater depth. Currently called virtual memory CD8+ T cells, they consist of a heterogeneous group of cells with memory characteristics, without any previous contact with their specific antigens. These cells were identified in mice, but a few years ago, a cell type with characteristics equivalent to the murine ones was described in healthy humans. In this review, we address the different aspects of its biology mainly developed in murine models and what is currently known about its cellular equivalent in humans.


Assuntos
Linfócitos T CD8-Positivos , Memória Imunológica , Humanos , Camundongos , Animais , Camundongos Endogâmicos C57BL
18.
J Immunol ; 183(6): 3591-7, 2009 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-19684081

RESUMO

IL-33, a new member of the IL-1 family, has been described as an important inducer of Th2 cytokines and mediator of inflammatory responses. In this study, we demonstrate that murine basophils sorted directly from the bone marrow, without prior exposure to IL-3 or Fc(epsilon)R cross-linking, respond to IL-33 alone by producing substantial amounts of histamine, IL-4, and IL-6. These cells express ST2 constitutively and generate a cytokine profile that differs from their IL-3-induced counterpart by a preferential production of IL-6. In vivo, IL-33 promotes basophil expansion in the bone marrow (BM) through an indirect mechanism of action depending on signaling through the beta(c) chain shared by receptors for IL-3, GM-CSF, and IL-5. IL-3 can still signal through its specific beta(IL-3) chain in these mutant mice, which implies that it is not the unique growth-promoting mediator in this setup, but requires IL-5 and/or GMCSF. Our results support a major role of the latter growth factor, which is readily generated by total BM cells as well as sorted basophils in response to IL-33 along with low amounts of IL-3. Furthermore, GM-CSF amplifies IL-3-induced differentiation of basophils from BM cells, whereas IL-5 that is also generated in vivo, affects neither their functions nor their growth in vitro or in vivo. In conclusion, our data provide the first evidence that IL-33 not only activates unprimed basophils directly, but also promotes their expansion in vivo through induction of GM-CSF and IL-3.


Assuntos
Basófilos/citologia , Proliferação de Células , Fatores Estimuladores de Colônias/biossíntese , Interleucinas/fisiologia , Animais , Células da Medula Óssea/citologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/biossíntese , Interleucina-3/biossíntese , Interleucina-33 , Interleucina-5 , Camundongos , Camundongos Knockout , Ativação Transcricional
19.
Front Immunol ; 12: 674016, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34367138

RESUMO

Immunosenescence is a physiological process that is associated with changes in the immune system, particularly among CD8 T-cells. Recent studies have hypothesized that senescent CD8 T-cells are produced with chronologic age by chronic stimulation, leading to the acquisition of hallmarks of innate-like T-cells. While conventional CD8 T-cells are quite well characterized, CD8 T-cells sharing features of NK cells and memory CD8 T-cells, are a newly described immune cell population. They can be distinguished from conventional CD8 T-cells by their combined expression of panKIR/NKG2A and Eomesodermin (E), a unique phenotype closely associated with IFN-γ production in response to innate stimulation. Here, we first provided new evidence in favor of the innate character of panKIR/NKG2A(+) E(+) CD8 T-cells in normal subjects, documenting their position at an intermediate level in the innateness gradient in terms of both innate IFN-γ production and diminished mitochondrial mass. We also revealed that CD8 E(+) panKIR/NKG2A(+) T-cells, hereafter referred to as Innate E(+) CD8 T-cells, exhibit increased senescent (CD27(-) CD28(-)) phenotype, compared to their conventional memory counterparts. Surprisingly, this phenomenon was not dependent on age. Given that inflammation related to chronic viral infection is known to induce NK-like marker expression and a senescence phenotype among CD8 T-cells, we hypothesized that innate E(+) CD8 T-cells will be preferentially associated with exacerbated cellular senescence in response to chronic alloantigen exposure or CMV infection. Accordingly, in a pilot cohort of stable kidney allotransplant recipients, we observed an increased frequency of the Innate E(+) CD8 T-cell subset, together with an exacerbated senescent phenotype. Importantly, this phenotype cannot be explained by age alone, in clear contrast to their conventional memory counterparts. The senescent phenotype in CD8 T-cells was further increased in cytomegalovirus (CMV) positive serology transplant recipients, suggesting that transplantation and CMV, rather than aging by itself, may promote an exacerbated senescent phenotype of innate CD8 T-cells. In conclusion, we proposed that kidney transplantation, via the setting of inflammatory stimuli of alloantigen exposure and CMV infection, may exogenously age the CD8 T-cell compartment, especially its innate component. The physiopathological consequences of this change in the immune system remain to be elucidated.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Imunidade Inata/imunologia , Memória Imunológica/imunologia , Imunossenescência/imunologia , Transplante de Rim , Adulto , Idoso , Idoso de 80 Anos ou mais , Infecções por Citomegalovirus/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transplante Homólogo
20.
Front Immunol ; 12: 744927, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34621275

RESUMO

Ischemia and reperfusion injury is an early inflammatory process during liver transplantation that impacts on graft function and clinical outcomes. Interleukin (IL)-33 is a danger-associated molecular pattern involved in kidney ischemia/reperfusion injury and several liver diseases. The aims were to assess whether IL-33 was released as an alarmin responsible for ischemia/reperfusion injury in a mouse model of warm hepatic ischemia, and whether this hypothesis could also apply in the setting of human liver transplantation. First, a model of warm hepatic ischemia/reperfusion was used in wild-type and IL-33-deficient mice. Severity of ischemia/reperfusion injury was assessed with ALT and histological analysis. Then, serum IL-33 was measured in a pilot cohort of 40 liver transplant patients. Hemodynamic postreperfusion syndrome, graft dysfunction (assessed by model for early allograft scoring >6), renal failure, and tissue lesions on time-zero biopsies were assessed. In the mouse model, IL-33 was constitutively expressed in the nucleus of endothelial cells, immediately released in response to hepatic pedicle clamping without neosynthesis, and participated in the recruitment of neutrophils and tissue injury on site. The kinetics of IL-33 in liver transplant patients strikingly matched the ones in the animal model, as attested by serum levels reaching a peak immediately after reperfusion, which correlated to clinical outcomes including postreperfusion syndrome, posttransplant renal failure, graft dysfunction, and histological lesions of ischemia/reperfusion injury. IL-33 was an independent factor of graft dysfunction with a cutoff of IL-33 at 73 pg/ml after reperfusion (73% sensitivity, area under the curve of 0.76). Taken together, these findings establish the immediate implication of IL-33 acting as an alarmin in liver I/R injury and provide evidence of its close association with cardinal features of early liver injury-associated disorders in LT patients.


Assuntos
Alarminas/imunologia , Interleucina-33/imunologia , Transplante de Fígado , Fígado/patologia , Traumatismo por Reperfusão/patologia , Alarminas/metabolismo , Animais , Estudos de Coortes , Humanos , Interleucina-33/metabolismo , Fígado/imunologia , Fígado/metabolismo , Camundongos , Projetos Piloto , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/metabolismo
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