Mecanismos de activación de las células T asesinas naturales invariantes (iNKT) / Mecanismos de ativação das células T assassinas naturais invariantes (iNKT) / Activation mechanisms of invariant natural killer T cells (iNKTs)

Aunque se ha logrado un conocimiento amplio acerca de las células T asesinas naturales (iNKT), aún no existe consenso sobre sus mecanismos de activación. Dichas células reconocen diferentes antígenos glicolipídicos presentados por medio de la molécula CD1d, los cuales pueden ser endógenos, exógenos derivados de organismos como bacterias y sintéticos desarrollados para aplicaciones clínicas. Existe mucho interés en entender cómo estas distintas variantes glicolipídicas inducen diferentes tipos de polarización, pero ha sido muy difícil llegar a un consenso, debido a que la respuesta depende de varios factores como la naturaleza, la internalización y el procesamiento de los glicolípidos. Además, la activación de las células iNKT la determinan el tipo y estado de activación de la célula presentadora de antígeno, las moléculas coestimuladoras, los mecanismos de transactivación y la localización de los complejos CD1d-glicolípido en distintas microrregiones de la membrana plasmática, como las balsas lipídicas. Esta revisión explora la evidencia sobre los factores que afectan la activación de las células iNKT con el fin de entender su potencial inmunomodulador.

A great amount of knowledge on natural killer T cells (iNKTs) is now available, but a consensus about their activation mechanisms has not been reached. These cells recognize different glycolipid antigens through the CD1d molecule. Such antigens may be endogenous, derived from bacteria (foreign) and synthetic, the latter have been developed for clinical applications. There exists much interest in understanding how these different glycolipid compounds induce different types of polarization, but it has been difficult to reach a consensus due to the fact that responses depend on different factors such as: the nature of the molecule, the internalization process and the presentation of the glycolipids. Moreover, activation of iNKT cells is determined by the type and state of the antigen presenting cell, the co-stimulatory molecules, the transactivation mechanisms and the location of the glycolipid-CD1d complexes on the plasma membrane, such as the lipid rafts. This review explores the evidence about the factors that affect activation of iNKT cells in order to understand their immune-modulatory potential.

Ainda que se conseguiu um conhecimento amplo a respeito das células T assassinas naturais (iNKT), ainda não existe consenso sobre seus mecanismos de ativação. Ditas células reconhecem diferentes antígenos glicolipídicos apresentados por meio da molécula CD1d, os quais pode ser: endógenos, exógenos derivados de organismos como bactérias e sintéticos desenvolvidos para aplicações clínicas. Existe muito interesse em entender como estas diferentes variantes glicolipídicas induzem diferentes tipos de polarização, mas foi muito difícil chegar a um consenso, devido a que a resposta depende de vários fatores como a natureza, a internalização e o processamento dos glicolípidos. Ademais, a ativação das células iNKT a determinam o tipo e estado de ativação da célula apresentadora de antígeno, as moléculas co-estimuladoras, os mecanismos de transativação e a localização dos complexos CD1d-glicolípido em diferentes microrregiões da membrana plasmática, como as balsas lipídicas. Esta revisão explora a evidência sobre os fatores que afetam a ativação das células iNKT com o fim de entender seu potencial imunomodulador.

Subpoblaciones de linfocitos B y su expresión de CD1d en pacientes con lupus eritematoso sistémico / B cell subsets and their expression of CD1d in patients with systemic lupus erythematosus

Resumen Introducción: Los linfocitos B (LB) se consideran el centro de la desregulación inmune en pacientes con lupus eritematoso sistémico (LES), principalmente, por su producción de autoanticuerpos. Recientemente, se demostró la existencia de LB, incluidos en los B transicionales, con capacidad reguladora (Breg) y fenotipo CD19+CD24hiCD38hi. En humanos se demostró la importancia de CD80 y CD86 en su función reguladora. El papel de CD1d aún no ha sido evaluado. Objetivo: Evaluar la frecuencia de LB maduros, memoria y transicionales, en controles y pacientes con LES, además de la expresión de CD1d y correlacionarla con la actividad de la enfermedad medida por SLEDAI (Systemic Lupus Erythematosus Disease Activity Index). Materiales y métodos: Se evaluó por citometría de flujo la frecuencia de subpoblaciones de LB basados en la expresión de CD19, CD24 y CD38, además de CD1d, en controles con otras enfermedades autoinmunes (OEA), individuos sanos y pacientes con LES, y se correlacionó con SLEDAI. Resultados: Se evidenció una disminución significativa en el porcentaje de LB de memoria en pacientes LES y OEA, sin alteraciones en las subpoblaciones de LB maduros y transicionales. La expresión de CD1d no evidenció diferencias significativas en ninguna de las subpoblaciones ni se correlacionó con SLEDAI. Conclusión: La disminución de la subpoblación de memoria fue previamente descrita en LES y se ha asociado a algunos tipos de tratamiento. Aunque CD1d se ha asociado a la función de Breg en murinos, no hubo diferencias significativas en su expresión en las subpoblaciones y queda por clarificar su papel en la función de las Breg humanas.

Abstract Introduction: B lymphocytes are considered the center of immune dysregulation in Systemic Lupus Erythematosus (SLE). It has recently been demonstrated that there is a B cell with regulatory capacities (Breg) included in transitional B lymphocytes with the phenotype CD19+CD24hiCD38hi. The importance of CD80 and CD86 in the regulatory function of the Bregs has been demonstrated in humans, but the role of CD1d has not been evaluated. Objective: To evaluate the frequency of mature, memory and transitional B cells in SLE patients and controls, the expression of CD1d among these cells, and its correlation with the activity of the disease measured using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Materials and methods: The frequency of the B cell subsets was evaluated by flow cytometry based on the expression of CD19, CD24 and CD38, as well as CD1d in these cells in SLE patients and controls, and were correlated with the activity of the disease measured using the SLEDAI. Results: A significant reduction in the percentage of memory B cells was observed in SLE patients and other autoimmune conditions, with no changes in the mature or transitional B cell subsets. Similarly, no significant differences were observed in the expression of CD1d in any of the subsets, nor was there any correlation with the SLEDAI. Conclusion: The reduction of the memory subset has been previously described in SLE, and has been associated with some types of treatment. The expression of CD1d in all the subsets was observed, but its role in the regulatory function of the CD19+CD24hiCD38hi cells is still not clear.

CD1d(hi)CD5⁺ B cells differentiate into antibody-secreting cells under the stimulation with calreticulin fragment

Calreticulin (CRT) is a multifunctional molecule in both intracellular and extracellular environment. We have previously found that a recombinant CRT fragment (rCRT/39-272) could modulate T cell-mediated immunity in mice via activation and expansion of CD1d(hi)CD5⁺ B cells as well as induction of CRT-specific regulatory antibodies. Antibody secreting cells (ASCs) are terminally differentiated B cells responsible for producing antibodies to participate in positive immune response as well as immune regulation. In this study, we demonstrate that rCRT/39-272 differentiates murine CD1d(hi)CD5⁺ B cells into ASCs marked by increased expression of plasma cell-associated transcription factors and production of polyreactive antibodies against DNA and CRT in vitro. Intraperitoneal administration of rCRT/39-272 augmented differentiation of CD1d(hi)CD5⁺ B cells into ASCs in naïve mice or mice with experimental autoimmune encephalomyelitis. Thus, we propose that ASC differentiation and subsequent antibody production of CD1d(hi)CD5⁺ B cells are key steps in CRT-mediated immunoregulation on inflammatory T cell responses.

The requirement of natural killer T-cells in tolerogenic APCs-mediated suppression of collagen-induced arthritis

TGF-beta-induced tolerogenic-antigen presenting cells (Tol-APCs) could induce suppression of autoimmune diseases such as collagen-induced arthritis (CIA) and allergic asthma. In contrast, many studies have shown that NKT cells are involved in the pathogenesis of Th1-mediated autoimmune joint inflammation and Th2-mediated allergic pulmonary inflammation. In this study, we investigated the effect of CD1d-restricted NKT cells in the Tol-APCs-mediated suppression of autoimmune disease using a murine CIA model. When CIA-induced mice were treated with Tol-APCs obtained from CD1d+/- or CD1d-/- mice, unlike CD1d+/- APCs, CD1d-/- Tol-APCs failed to suppress CIA. More specifically, CD1d-/- Tol-APCs failed to suppress the production of inflammatory cytokines and the induction of Th2 responses by antigen-specific CD4 T cells both in vitro and in vivo. Our results demonstrate that the presence of CD1d-restricted NKT cells is critical for the induction of Tol-APCs-mediated suppression of CIA.

Papel de las células nkt invariantes en la respuesta inmune anti-viral: [revisión] / Role of invariant nkt cells in the anti-viral immune response: [review]

Las células T asesinas naturales con receptor de células T invariante y restringidas por la molécula CD1d (iNKT) son un subgrupo de linfocitos con potente actividad inmunorreguladora; su respuesta casi inmediata y la capacidad de producir citoquinas tanto Th1 como Th2 son factores determinantes en el desarrollo de la respuesta inmune innata y adaptativa. El papel fisiológico de las células iNKT se ha documentado ampliamente en la respuesta anti-tumoral, el desarrollo de la tolerancia en los órganos inmunoprivilegiados y el control de las reacciones autoinmunes. A pesar de la demostrada potencia inmunomoduladora de las células iNKT, hasta el momento se conoce poco de su acción en la respuesta inmune anti-infecciosa, en particular en el ser humano y contra los virus patógenos. Este artículo sintetiza los resultados de una búsqueda en las principales bases de datos biomédicas (Pubmed, Medline y OVID), e incluye los estudios realizados para caracterizar estas células y evaluar su papel en la interacción del hospedero con los virus. Las células iNKT participan en la respuesta inmune antiviral, aunque de una manera diferente según el tipo de virus; incluso, podrían estar comprometidas en los daños mediados por mecanismos inmunes. En el ser humano, las células iNKT son aparentemente esenciales en la respuesta inmune contra el virus Varicela Zoster, mientras que todavía hay controversia sobre su función en el control de otros virus. Los modelos animales han aportado las primeras evidencias sobre el potencial de la manipulación terapéutica específica de este subgrupo de linfocitos.

Natural killer T cells with an invariant T-cell receptor and restricted by CD1d (iNKT) are a subgroup of lymphocytes with a very strong immunoregulatory potential; their quick response and their ability to produce Th1 and Th2 cytokines are determinant factors that influence the development of innate and adaptive immune responses. The physiological role of iNKT cells has been well documented in anti-tumor immune responses, the development of tolerance in immune-privileged organs and the control of autoimmune diseases. Despite the fact that the immunoregulatory potential of these cells has been well documented, less is known regarding their role in the immune response against infectious agents, in particular to human pathogenic viruses. This paper synthesizes the search in the most important biomedical data bases (Pubmed, Medline, OVID), including studies on the phenotypic characterization of these cells and functional studies that evaluated their role in the interaction between hosts and viruses. iNKT cells have a heterogeneous participation during the anti-viral immune responses, depending on the type of virus; indeed, in some instances the iNKT-cell responses can be involved in the tissue damage associated to the anti-viral responses. In humans, iNKT cells are apparently essential for an effective immune response against Varicella Zoster virus, while it is still controversial their role in the control of other viral infections. Studies in animal models have shown the first evidences on the therapeutic potential of this lymphocyte subpopulation.