The induction of SHP-1 degradation by TAOK3 ensures the responsiveness of T cells to TCR stimulation.

Thousand-and-one-amino acid kinase 3 (TAOK3) is a serine and threonine kinase that belongs to the STE-20 family of kinases. Its absence reduces T cell receptor (TCR) signaling and increases the interaction of the tyrosine phosphatase SHP-1, a major negative regulator of proximal TCR signaling, with the kinase LCK, a component of the core TCR signaling complex. Here, we used mouse models and human cell lines to investigate the mechanism by which TAOK3 limits the interaction of SHP-1 with LCK. The loss of TAOK3 decreased the survival of naïve CD4+ T cells by dampening the transmission of tonic and ligand-dependent TCR signaling. In mouse T cells, Taok3 promoted the secretion of interleukin-2 (IL-2) in response to TCR activation in a manner that depended on Taok3 gene dosage and on Taok3 kinase activity. TCR desensitization in Taok3-/- T cells was caused by an increased abundance of Shp-1, and pharmacological inhibition of Shp-1 rescued the activation potential of these T cells. TAOK3 phosphorylated threonine-394 in the phosphatase domain of SHP-1, which promoted its ubiquitylation and proteasomal degradation. The loss of TAOK3 had no effect on the abundance of SHP-2, which lacks a residue corresponding to SHP-1 threonine-394. Modulation of SHP-1 abundance by TAOK3 thus serves as a rheostat for TCR signaling and determines the activation threshold of T lymphocytes.

TAOK3 limits age-associated inflammation by negatively modulating macrophage differentiation and their production of TNFα.

BACKGROUND: Human aging is characterized by a state of chronic inflammation, termed inflammaging, for which the causes are incompletely understood. It is known, however, that macrophages play a driving role in establishing inflammaging by promoting pro-inflammatory rather than anti-inflammatory responses. Numerous genetic and environmental risk factors have been implicated with inflammaging, most of which are directly linked to pro-inflammatory mediators IL-6, IL1Ra, and TNFα. Genes involved in the signaling and production of those molecules have also been highlighted as essential contributors. TAOK3 is a serine/threonine kinase of the STE-20 kinase family that has been associated with an increased risk of developing auto-immune conditions in several genome-wide association studies (GWAS). Yet, the functional role of TAOK3 in inflammation has remained unexplored. RESULTS: We found that mice deficient in the serine/Threonine kinase Taok3 developed severe inflammatory disorders with age, which was more pronounced in female animals. Further analyses revealed a drastic shift from lymphoid to myeloid cells in the spleens of those aged mice. This shift was accompanied by hematopoietic progenitor cells skewing in Taok3-/- mice that favored myeloid lineage commitment. Finally, we identified that the kinase activity of the enzyme plays a vital role in limiting the establishment of proinflammatory responses in macrophages. CONCLUSIONS: Essentially, Taok3 deficiency promotes the accumulation of monocytes in the periphery and their adoption of a pro-inflammatory phenotype. These findings illustrate the role of Taok3 in age-related inflammation and highlight the importance of genetic risk factors in this condition.

T-cell-expressed proprotein convertase FURIN inhibits DMBA/TPA-induced skin cancer development.

Proprotein convertases (PCSK) have a critical role in the body homeostasis as enzymes responsible for processing precursor proteins into their mature forms. FURIN, the first characterized member of the mammalian PCSK family, is overexpressed in multiple malignancies and the inhibition of its activity has been considered potential cancer treatment. FURIN has also an important function in the adaptive immunity, since its deficiency in T cells causes an impaired peripheral immune tolerance and accelerates immune responses. We addressed whether deleting FURIN from the immune cells would strengthen anticancer responses by subjecting mouse strains lacking FURIN from either T cells or macrophages and granulocytes to the DMBA/TPA two-stage skin carcinogenesis protocol. Unexpectedly, deficiency of FURIN in T cells resulted in enhanced and accelerated development of tumors, whereas FURIN deletion in macrophages and granulocytes had no effect. The epidermises of T-cell-specific FURIN deficient mice were significantly thicker with more proliferating Ki67+ cells. In contrast, there were no differences in the numbers of the T cells. The flow cytometric analyses of T-cell populations in skin draining lymph nodes showed that FURIN T-cell KO mice have an inherent upregulation of early activation marker CD69 as well as more CD4+CD25+Foxp3+ positive T regulatory cells. In the early phase of tumor promotion, T cells from the T-cell-specific FURIN knockout animals produced more interferon gamma, whereas at later stage the production of Th2- and Th17-type cytokines was more prominent than in wild-type controls. In conclusion, while PCSK inhibitors are promising therapeutics in cancer treatment, our results show that inhibiting FURIN specifically in T cells may promote squamous skin cancer development.

Factores genéticos, inmunológicos y ambientales asociados a la autoinmunidad / Genetic, immunologic and environmental factors associated with autoimmunity

La autoinmunidad se caracteriza por una pérdida de la tolerancia inmunológica que produce la destrucción de células y tejidos propios. El sistema del complejo mayor de histocompatibilidad posee una fuerte asociación con las enfermedades autoinmunes aunque determinados genes que codifican para citoquinas y moléculas coestimuladoras incrementan la susceptibilidad genética. Estudios de concordancia entre gemelos monocigóticos demuestran el papel de los factores ambientales en la aparición de las enfermedades autoinmunes. A pesar de los avances científicos producidos en esta área de investigación, los mecanismos subyacentes de estas afecciones son desconocidos. El objetivo de este trabajo es exponer de forma sintetizada el papel de los factores genéticos, inmunológicos y ambientales en la autoinmunidad

The autoimmunity is characterized by a loss of immunologic tolerance producing the destruction of cells and own tissues. The major complex system of histocompatibility has a close association with the autoimmune diseases although determined genes codifying for cytokines and co-stimulators molecules increase the genetic susceptibility. Concordance studies among monozygotic twins demonstrate the role of environmental factors in appearance of autoimmune diseases. Despite the scientific advances achieved in this research field, the underlying mechanisms of these affections are unknown. The objective of present paper is to expose in a summarized way the role of the genetic, immunologic and environmental factors in autoimmunity

Comportamiento de los alelos HLA-DQB1*02 y HLA-DQB1*03 en pacientes con diagnóstico presuntivo de enfermedad celíaca / Behavior of HLA-DQB1*02 and HLA-DQB1*03 alleles in patients with a presumptive diagnosis of celiac disease

La enfermedad celíaca (EC) es autoinmune y se observa en individuos genéticamente predispuestos, se caracteriza por la intolerancia a determinadas proteínas llamadas gluten (gliadinas y gluteínas) que se encuentran en el trigo, el centeno y la cebada. Se sabe que existe una asociación del sistema HLA y la enfermedad celíaca (HLA-DQ2/HLA-DQ8), pero no existen estudios cubanos acerca de esa asociación por lo que nos propusimos analizar el comportamiento de los alelos DQB1*02 y DQB1*03 mediante un estudio analítico observacional en 65 pacientes con diagnóstico presuntivo de enfermedad celíaca con el objetivo de incluir la detección de estos alelos en el esquema diagnóstico de esta compleja enfermedad. Se halló que los individuos portadores del alelo DQB1*02 (OR: 2,26) fueron más susceptibles de padecer la enfermedad que los no portadores, que el 60 por ciento de los presuntos pacientes con enfermedad celíaca presentaron el alelo HLA-DQ2 y el 3 por ciento, el alelo HLA-DQ8. Se concluyóque el genotipaje HLA-DQ2/HLA-DQ8 es de gran utilidad para el diagnóstico de enfermedad celíaca

The celiac disease (CD) is autoimmune and it is present in genetically predisposed subjects, characterized by the intolerance to determined proteins present in wheat, rye and barley: called gluten and gliadin. It is known that there is an association between HLA-system and celiac disease (HLA-DQ2/HLA-DQ8), but there aren't Cuban studies on this association, thus we analyzed the behavior of DQB1*02 and DQB1*03 alleles by means of an observational and analytical study in 65 patients with a presumptive diagnosis of celiac disease to include its detection in the diagnostic scheme of this complex disease. There was found that subjects carriers of the DQB1*02 allele (OR: 2,26) were more susceptible to suffer this disease than those non-carriers, that the 60 percent of the supposed patients presenting with the celiac disease had the HLA-DQ2 allele and the 3 percent had the HLA-DQ8 allele. We conclude that the HLA-DQ2/HLA-DQ8 genotyping is very useful for the diagnosis of the celiac disease

Prevalencia del virus de la hepatitis C en las unidades de hemodiálisis de la región occidental cubana / Hepatitis C virus present in hemodialysis units from Cuban western region

La población de hemodiálisis constituye un grupo de alto riesgo en el caso de la infección por el virus de la hepatitis C. Se realizó un análisis multicéntrico de la prevalencia de la infección por el virus de la hepatitis C en las unidades de diálisis de la región occidental aplicando las técnicas serológicas y moleculares, y se observó si existían diferencias significativas en cuanto a la aplicación de ambas técnicas. Se obtuvieron valores elevados de prevalencia de anticuerpos anti-VHC en todas las unidades de diálisis (76 %), así como la calculada aplicando la detección del ARN viral (55 %). No se hallaron diferencias significativas (k) en cuanto a la aplicación de ambas técnicas en la mayoría de las unidades de diálisis analizadas. La elevada prevalencia viral se asocia a la transmisión nosocomial provocada por el incumplimiento de las normas de precaución universal establecidas.

Hemodialysis population is a high risk group related to hepatitis C virus infection. Authors made a multicenter analysis on infection prevalence of hepatitis C virus in dialysis units of western region applying serologic and molecular techniques observing if there significant differences as regards the application of both techniques. We achieved high values of anti-CHV antibody prevalence in all dialysis units (76 %) as well as the estimated prevalence applying viral RNA detection (55 %). There were not significant differences (k) as regards application of both techniques in most of analyzed dialysis units. Viral high prevalence is associated with nosocomial transmission caused by no-fulfillment of established universal precaution standards.

Prevalencia de anticuerpos anti-VHC y del antígeno de superficie de la hepatitis B en pacientes tratados con hemodiálisis / Prevalence of anti-HCV antibodies and of the hepatitis B surface antigen in patients treated with hemodialysis

Se estudiaron 108 pacientes con tratamiento de hemodiálisis para determinar la prevalencia de anticuerpos contra el virus de la hepatitis C (anti-VHC) y del antígeno de superficie de la hepatitis B (HBsAg) empleando la tecnología SUMA. Se obtuvo elevada prevalencia de anticuerpos contra el virus de la hepatitis C (90 por ciento) y menor prevalencia del HBsAg (4 por ciento). Se hallaron títulos protectores de anticuerpos anti-HBsAg en el 91 por ciento de los pacientes. Se observó que los pacientes con niveles de anticuerpos de 10 UI/L resultaron protegidos lo que se corresponde con una respuesta efectiva a nuestro esquema de vacunación y con mejores resultados que lo normalmente reportado para este tipo de paciente (100 UI/L). Se presentaron valores persistentemente normales de actividad enzimática de la enzima glutámico-pirúvica (TGP) en el 65 por ciento de los pacientes, lo que podría indicar una enfermedad crónica y corrobora la frecuente disminución que se observa en la actividad enzimática de la TGP.

108 hemodialysis patients were studied to determine the prevalence of antibodies against hepatitis C virus (anti-HCV) and of the hepatitis B surface antigen (HBsAg) by using the SUMA technology. It was obtained an elevated prevalence of antibodies against the hepatitis C virus (90 percent) and a lower prevalence of of HBsAg (4 percent). Titres protecting anti-HBsAg antibodies were found in 91 percent of the patients. It was observed that the patients with antibody levels of 10 UI/L were protected, which corresponds to an effective response to our vaccination scheme and to better results than the ones normally reported for this type of patient (100 UI/L). Persistently normal values of the enzymatic activity of the glutamic piruvic enzyme (GPT) were present in 65 percent of the patients, which could indicate a chronic disease and corroborate the frequent decrease observed in the enzymatic activity of GPT.