Metformin Restrains the Proliferation of CD4+ T Lymphocytes by Inducing Cell Cycle Arrest in Normo- and Hyperglycemic Conditions.

CD4+ T lymphocytes play a key role in the modulation of the immune response by orchestrating both effector and regulatory functions. The effect of metformin on the immunometabolism of CD4+ T lymphocytes has been scarcely studied, and its impact under high glucose conditions, particularly concerning effector responses and glucose metabolism, remains unknown. This study aims to evaluate the effect of metformin on the modulation of the effector functions and glucose metabolism of CD4+ T lymphocytes under normo- and hyperglycemic conditions. CD4+ T lymphocytes, obtained from peripheral blood from healthy volunteers, were anti-CD3/CD28-activated and cultured for 4 days with three concentrations of metformin (0.1 mM, 1 mM, and 5 mM) under normoglycemic (5.5 mM) and hyperglycemic (25 mM) conditions. Effector functions such as proliferation, cell count, cell cycle analysis, activation markers and cytokine secretion were analyzed by flow cytometry. Glucose uptake was determined using the 2-NBDG assay, and levels of glucose, lactate, and phosphofructokinase (PFK) activity were assessed by colorimetric assays. Metformin at 5 mM restrained the cell counts and proliferation of CD4+ T lymphocytes by arresting the cell cycle in the S/G2 phase at the beginning of the cell culture, without affecting cell activation, cytokine production, and glucose metabolism. In fact, CD69 expression and IL4 secretion by CD4+ T lymphocytes was higher in the presence of 5 mM than the untreated cells in both glucose conditions. Overall, metformin inhibited proliferation through mechanisms associated with cell cycle arrest, leading to an increase in the S/G2 phases at the expense of G1 in activated CD4+ T lymphocytes in normo- and hyperglycemic conditions. Despite the cell cycle arrest, activated CD4+ T lymphocytes remained metabolically, functionally, and phenotypically activated.

HIV-Induced Thymic Insufficiency and Aging-Related Immunosenescence on Immune Reconstitution in ART-Treated Patients.

The mechanisms underlying unsatisfactory immune reconstitution in HIV-1 positive patients under ART have not been fully elucidated, even after years of investigation. Thus, this study aimed to assess the correlation between age and thymic production profile, and its influence on inadequate immunological recovery. Here, 44 ART-treated patients with undetectable plasma HIV-1 load (<40 copies/mL) were classified as 31 immunological responders (IR) and 13 immunological non-responders (INR), according to their CD4+ T-cell count after 18 months of ART. The thymic function was assessed by identifying recent thymic emigrants (RTEs) CD4+ T cells (CD4+/CD45RA+CD31+) in PBMCs using flow cytometry. Clinical data were also analyzed from medical records. The INR group showed a higher age at ART initiation (41 ± 3.0) compared to the IR (33.7 ± 2.1) group (p = 0.041). Evaluating RTE CD4+ T-cells, we observed a lower percentage in the INR group (19.5 ± 6.3) compared to the IR group (29.9 ± 11.5) (p = 0.012). There was a strong negative correlation between age at ART initiation and RTE CD4+ T-cells in INRs (r = -0.784, p = 0.004). Our study has highlighted the thymic insufficiency and aging-related immunosenescence with unsatisfactory immunological recovery during ART in HIV-1 positive patients.

Corrigendum: Cross-reactive humoral and CD4+ T cell responses to Mu and Gamma SARS-CoV-2 variants in a Colombian population.

[This corrects the article DOI: 10.3389/fimmu.2023.1241038.].

Cross-reactive humoral and CD4+ T cell responses to Mu and Gamma SARS-CoV-2 variants in a Colombian population.

The SARS CoV-2 antibody and CD4+ T cell responses induced by natural infection and/or vaccination decline over time and cross-recognize other viral variants at different levels. However, there are few studies evaluating the levels and durability of the SARS CoV-2-specific antibody and CD4+ T cell response against the Mu, Gamma, and Delta variants. Here, we examined, in two ambispective cohorts of naturally-infected and/or vaccinated individuals, the titers of anti-RBD antibodies and the frequency of SARS-CoV-2-specific CD4+ T cells up to 6 months after the last antigen exposure. In naturally-infected individuals, the SARS-CoV-2 antibody response declined 6 months post-symptoms onset. However, the kinetic observed depended on the severity of the disease, since individuals who developed severe COVID-19 maintained the binding antibody titers. Also, there was detectable binding antibody cross-recognition for the Gamma, Mu, and Delta variants, but antibodies poorly neutralized Mu. COVID-19 vaccines induced an increase in antibody titers 15-30 days after receiving the second dose, but these levels decreased at 6 months. However, as expected, a third dose of the vaccine caused a rise in antibody titers. The dynamics of the antibody response upon vaccination depended on the previous SARS-CoV-2 exposure. Lower levels of vaccine-induced antibodies were associated with the development of breakthrough infections. Vaccination resulted in central memory spike-specific CD4+ T cell responses that cross-recognized peptides from the Gamma and Mu variants, and their duration also depended on previous SARS-CoV-2 exposure. In addition, we found cross-reactive CD4+ T cell responses in unexposed and unvaccinated individuals. These results have important implications for vaccine design for new SARS-CoV-2 variants of interest and concern.

P2RX7 signaling drives the differentiation of Th1 cells through metabolic reprogramming for aerobic glycolysis.

Introduction: This study provides evidence of how Th1 cell metabolism is modulated by the purinergic receptor P2X7 (P2RX7), a cation cannel activated by high extracellular concentrations of adenosine triphosphate (ATP). Methods: In vivo analysis was performed in the Plasmodium chabaudi model of malaria in view of the great relevance of this infectious disease for human health, as well as the availability of data concerning Th1/Tfh differentiation. Results: We show that P2RX7 induces T-bet expression and aerobic glycolysis in splenic CD4+ T cells that respond to malaria, at a time prior to Th1/Tfh polarization. Cell-intrinsic P2RX7 signaling sustains the glycolytic pathway and causes bioenergetic mitochondrial stress in activated CD4+ T cells. We also show in vitro the phenotypic similarities of Th1-conditioned CD4+ T cells that do not express P2RX7 and those in which the glycolytic pathway is pharmacologically inhibited. In addition, in vitro ATP synthase blockade and the consequent inhibition of oxidative phosphorylation, which drives cellular metabolism for aerobic glycolysis, is sufficient to promote rapid CD4+ T cell proliferation and polarization to the Th1 profile in the absence of P2RX7. Conclusion: These data demonstrate that P2RX7-mediated metabolic reprograming for aerobic glycolysis is a key event for Th1 differentiation and suggest that ATP synthase inhibition is a downstream effect of P2RX7 signaling that potentiates the Th1 response.

Thymic Exhaustion and Increased Immune Activation Are the Main Mechanisms Involved in Impaired Immunological Recovery of HIV-Positive Patients under ART.

Decades of studies in antiretroviral therapy (ART) have passed, and the mechanisms that determine impaired immunological recovery in HIV-positive patients receiving ART have not been completely elucidated yet. Thus, T-lymphocytes immunophenotyping and cytokines levels were analyzed in 44 ART-treated HIV-positive patients who had a prolonged undetectable plasma viral load. The patients were classified as immunological non-responders (INR = 13) and immunological responders (IR = 31), according to their CD4+ T cell levels. Evaluating pre-CD4+ levels, we observed a statistically significant trend between lower CD4+ T cell levels and INR status (Z = 3.486, p < 0.001), and during 18 months of ART, the CD4+ T cell levels maintained statistical differences between the INR and IR groups (WTS = 37.252, p < 0.001). Furthermore, the INRs were associated with an elevated age at ART start; a lower pre-treatment CD4+ T cell count and a percentage that remained low even after 18 months of ART; lower levels of recent thymic emigrant (RTE) CD4+ T cell (CD45RA + CD31+) and a naïve CD4+ T cell (CD45RA + CD62L+); higher levels of central memory CD4+ T cells (CD45RA-CD62L+); and higher immune activation by CD4+ expressing HLA-DR+ or both (HLA-DR+ and CD38+) when compared with IRs. Our study demonstrates that thymic exhaustion and increased immune activation are two mechanisms substantially implicated in the impaired immune recovery of ART-treated HIV patients.

Epigenetic regulation of T cells by Polycomb group proteins.

T cells are critical for pathogen elimination, tumor surveillance, and immunoregulation. The development, activation, and differentiation of CD8 and CD4 T lymphocytes are a set of complex and dynamically regulated events that require epigenetic control. The Polycomb group (PcG) proteins are a family of diverse and evolutionarily conserved epigenetic modulators fundamentally involved in several mechanisms of gene regulation. PcG proteins can assemble into distinct repressor complexes, the two most understood being the Polycomb Repressor Complex (PRC)1 and PRC2, which control chromatin structure mainly through posttranslational modifications of histones. In this review, we will summarize the most recent findings regarding the diverse roles performed by PcG proteins in T cell biology. We will focus on PRC1 and PRC2 contribution to the regulation of T cell development in the thymus, CD4 T cell differentiation in helper or regulatory phenotypes and CD8 T cell fate commitment in the context of infections and cancer, highlighting the known mechanisms and knowledge gaps that still need to be addressed.

Platelets modulate CD4+ T-cell function in COVID-19 through a PD-L1 dependent mechanism.

Severe COVID-19 is associated with a systemic inflammatory response and progressive CD4+ T-cell lymphopenia and dysfunction. We evaluated whether platelets might contribute to CD4+ T-cell dysfunction in COVID-19. We observed a high frequency of CD4+ T cell-platelet aggregates in COVID-19 inpatients that inversely correlated with lymphocyte counts. Platelets from COVID-19 inpatients but not from healthy donors (HD) inhibited the upregulation of CD25 expression and tumour necrosis factor (TNF)-α production by CD4+ T cells. In addition, interferon (IFN)-γ production was increased by platelets from HD but not from COVID-19 inpatients. A high expression of PD-L1 was found in platelets from COVID-19 patients to be inversely correlated with IFN-γ production by activated CD4+ T cells cocultured with platelets. We also found that a PD-L1-blocking antibody significantly restored platelets' ability to stimulate IFN-γ production by CD4+ T cells. Our study suggests that platelets might contribute to disease progression in COVID-19 not only by promoting thrombotic and inflammatory events, but also by affecting CD4+ T cells functionality.

CD4+ T Cell Regulatory Network Underlies the Decrease in Th1 and the Increase in Anergic and Th17 Subsets in Severe COVID-19.

In this model we use a dynamic and multistable Boolean regulatory network to provide a mechanistic explanation of the lymphopenia and dysregulation of CD4+ T cell subsets in COVID-19 and provide therapeutic targets. Using a previous model, the cytokine micro-environments found in mild, moderate, and severe COVID-19 with and without TGF-ß and IL-10 was we simulated. It shows that as the severity of the disease increases, the number of antiviral Th1 cells decreases, while the the number of Th1-like regulatory and exhausted cells and the proportion between Th1 and Th1R cells increases. The addition of the regulatory cytokines TFG-ß and IL-10 makes the Th1 attractor unstable and favors the Th17 and regulatory subsets. This is associated with the contradictory signals in the micro-environment that activate SOCS proteins that block the signaling pathways. Furthermore, it determined four possible therapeutic targets that increase the Th1 compartment in severe COVID-19: the activation of the IFN-γ pathway, or the inhibition of TGF-ß or IL-10 pathways or SOCS1 protein; from these, inhibiting SOCS1 has the lowest number of predicted collateral effects. Finally, a tool is provided that allows simulations of specific cytokine environments and predictions of CD4 T cell subsets and possible interventions, as well as associated secondary effects.

An exacerbated metabolism and mitochondrial reactive oxygen species contribute to mitochondrial alterations and apoptosis in CD4 T cells during the acute phase of Trypanosoma cruzi infection.

Chagas disease caused by Trypanosoma cruzi parasite is an endemic infection in America. It is well known that T. cruzi causes a strong immunosuppression during the acute phase of infection. However, it is not clear whether T. cruzi infection is related to metabolic alterations in CD4 T cells that prevent downstream effector function. Here, we evaluated the CD4 T cell metabolic and mitochondrial profiles from non-infected (NI), acute phase (AP) and chronic phase (CP) T. cruzi infected mice. CD4 T cells from all groups showed increased glucose uptake after stimulation. Moreover, the bioenergetic analysis revealed a rise in glycolysis and a higher oxidative metabolism in CD4 T cells from the AP. These cells showed increased proton leak and uncoupling protein 3 (UCP3) expression that correlated with mitochondrial ROS (mROS) accumulation, mitochondrial membrane potential (MMP) depolarization and expression of PD-1. In addition, CD4 T cells with mitochondrial alteration displayed an activated phenotype, and were less functional and more prone to apoptosis. In contrast, mitochondrial alterations were not observed during in vivo activation of CD4 T cells in a model of OVA-immunization. The Mn-superoxide dismutase (SOD2) expression, which is involved in mROS detoxification, was increased during the AP and CP of infection. Remarkably, the apoptosis observed in CD4 T cells with MMP depolarization was prevented by incubation with N-acetyl cysteine (NAC). Thus, our results showed that infection triggered an exacerbated metabolism together with mROS production in CD4 T cells from the AP of infection. However, antioxidant availability may not be sufficient to avoid mitochondrial alterations rendering these cells more susceptible to apoptosis. Our investigation is the first to demonstrate an association between a disturbed metabolism and an impaired CD4 T cell response during T. cruzi infection.

Increased Frequency of Memory CD4+ T-Cell Responses in Individuals With Previously Treated Extrapulmonary Tuberculosis.

Extrapulmonary TB (EPTB) occurs with increased frequency in persons with underlying immunodeficiency. Even after recovery from acute illness, differences in immune phenotype and activation persist. Studies defining characteristics of immune responses after recovery from extrapulmonary TB may provide insights into factors that increase TB risk. We performed two case-control studies (in the United States and Brazil) among HIV-seronegative adults with previous EPTB (n = 9; 25), previous pulmonary TB (n = 7; 25), latent M. tuberculosis (Mtb) infection (n = 11; 25), and uninfected TB contacts (n = 10; 25). We assessed the frequency of dual CD4+ interferon-γ and tumor necrosis factor-α responses after stimulation with overlapping Mtb peptides from ESAT-6 or CFP-10, or gamma-irradiated Mtb H37Rv, proliferative responses to Mtb antigens, T-regulatory cell (Treg) frequency and phenotype. In both study populations, individuals with prior EPTB had the highest frequency of intracellular cytokine-producing cells in response to Mtb antigens (p < 0.05; p <.0001). Persons with prior EPTB in Brazil had the highest levels of CD4 proliferation to Mtb antigens (p < 0.0001), and the highest expression of CD39 on Tregs (p < 0.0001). Individuals with treated EPTB maintained high frequencies of Mtb-specific memory responses and active Treg cells, suggesting that susceptibility to EPTB occurs despite the ability to develop and maintain enhanced adaptive immune responses.

Immunological recovery failure in cART-treated HIV-positive patients is associated with reduced thymic output and RTE CD4+ T cell death by pyroptosis.

Despite more than three decades of studies and advances in combination antiretroviral therapy (cART) against human immunodeficiency virus (HIV), the mechanisms that precisely determine immune reconstitution failure have not been completely elucidated yet. Thus, this study aimed to investigate the thymic function, immune activation, and cell death by pyroptosis and apoptosis in virologically suppressed HIV-positive patients receiving cART. Immunophenotyping analyses were performed in 57 cART-treated HIV-infected patients with undetectable plasma viral load, who were classified as immunological nonresponders (INR = 29) and immunologic responders (IR = 28). Sociodemographic and clinical data were also assessed from medical records. Twelve healthy volunteers were also included in this study. The INR showed lower pretreatment CD4+ T cell count that remained low even after 1 yr of treatment, lower CD4/CD8 ratio, lower percentage of recent thymic emigrant (RTE) CD4+ T cell (CD45RA+CD31+) and naïve CD4+ T cell (CD45RA+CD62L+), higher levels of effector memory CD4+ T cells (CD45RA-CD62L-), and higher pyroptosis levels of RTE CD4+ T cells (CD31+FLICA-Caspase1+) when compared with IR. Our findings indicate that reduced thymic function and RTE CD4+ T cell death by pyroptosis are the major mechanisms of immunological recovery failure in HIV-infected patients receiving cART.

Effervescent Glutamine Formulation Improves the Beneficial Effects of Antiretroviral Therapies on Immune Function in HIV/AIDS Carrier Patients.

The impact of oral supplementation with an effervescent glutamine formulation on the beneficial effects of antiretroviral therapies was evaluated in people living with HIV/AIDS. For this purpose, 12 HIV/AIDS carrier patients with CD4+ T cell counts <500, and who had received the same antiretroviral therapy for at least 1 year before starting this investigation were selected. The patients were required to dissolve the effervescent glutamine formulation (supplied in sachets) in water immediately before oral ingestion (12.4 g), once a day, after lunch or after dinner during 30 days. CD4+ T cell counts, complete blood cell counts, serum cytokines, and amino acids levels were quantified; biochemical and toxicological measurements were performed. The numbers of CD4+ T cells were increased (P < .05), and the serum C-reactive protein levels decreased (P < .01) after the administration of effervescent glutamine formulation. Serum levels of interferon-gamma inducible protein-10, RANTES, and macrophage inflammatory protein-1ß were decreased after the treatment with effervescent glutamine formulation. No changes were observed in the serum levels of amino acids, hematological, toxicological, and biochemical parameters. In conclusion, the treatment during 30 days with effervescent glutamine formulation was well tolerated, promoted reduction of inflammation, and improved the beneficial effects of antiretroviral therapies in HIV/AIDS carrier patients.

Aspectos clínicos y de laboratorio en pacientes con diagnóstico tardío de SIDA / Clinical and laboratory findings in patients with late diagnosis of AIDS

RESUMEN Introducción: El retraso diagnóstico de la infección por SIDA constituye un problema de gran magnitud con importantes repercusiones para los propios infectados y para la sociedad en general. Objetivos: Caracterizar a los pacientes con diagnóstico tardío de infección por VIH y su evolución a los 6 meses del diagnóstico. Material y Métodos: Se realizó un estudio longitudinal de corte prospectivo que incluyó 248 casos con diagnóstico positivo de infección por VIH durante su ingreso o en la consulta de infectología del Instituto de Medicina Tropical "Pedro Kourí" desde enero de 2015 hasta diciembre de 2016, los que se dividieron en dos grupos de comparación, según diagnóstico tardío (n=79) o no (n=169) de la enfermedad. Resultados: La edad avanzada y el sexo masculino fueron factores relacionados con el diagnóstico tardío de la infección por VIH. La fiebre (31,7%) y los síntomas respiratorios (20,3%) fueron las formas más frecuentes de presentación, mientras que la neumonía por Pneumocystis jirovecii fue la enfermedad con más incidencia en el momento del diagnóstico. La mitad de los pacientes se encontraban con inmunodepresión severa en el momento del diagnóstico. Los pacientes con diagnóstico tardío mostraron una supervivencia significativamente menor a los 6 meses del diagnóstico en comparación con los pacientes con diagnóstico precoz. La carga viral y el nivel de linfocitos CD4 fueron parámetros de laboratorio con un alto valor predictivo de mortalidad. Conclusiones: El diagnóstico tardío de infección por VIH conlleva un alto riesgo de mortalidad, mayor en aquellos con afectación de la carga viral y el nivel de linfocitos T CD4+.

ABSTRACT Introduction: Late diagnosis of HIV is a major problem with important consequences for the people infected with this virus and the society in general. Objectives: To characterize patients with late diagnosis of HIV infection and their evolution six months after diagnosis. Material and Methods: We conducted a prospective longitudinal study which included 248 cases with positive diagnosis of HIV infection during admission at the Pedro Kourí Tropical Medicine Institute between January 2015 and December 2016. They were divided into two comparison groups which included patients with late diagnosis (n=79) and those with no late diagnosis (n=169) of the disease. Results: Advanced age and male sex were factors related to the late diagnosis of HIV infection. Fever (31.7%) and respiratory symptoms (20.3%) were the most frequent forms of presentation, whereas Pneumocystis jirovecii pneumonia was the disease with the highest incidence at the time of diagnosis. Half of the patients were found to have severe immunosuppression at the time of diagnosis. Patients with late diagnosis showed a significantly diminished survival six months after being diagnosed compared with those patients with early diagnosis. Viral load and CD4+ T count were laboratory parameters with a high predictive value of mortality. Conclusions: Late diagnosis of HIV leads to a high risk of mortality, which is higher in those with affectation of the viral load and low CD4+ T cell count.

Características clínicas de pacientes con Virus de Inmunodeficiencia Humana. Hospital General Docente "Enrique Cabrera" / Clinical characteristics of patients with Human Immunodeficiency Virus. Enrique Cabrera General Teaching Hospital

RESUMEN Introducción: La atención de pacientes con VIH se realiza actualmente en Cuba de forma descentralizada; cada vez es mayor el número de casos ingresados en hospitales generales. Objetivo: Determinar características clínicas de pacientes con VIH ingresados en el Hospital General Docente "Enrique Cabrera". Material y Métodos: Se realizó una investigación descriptiva retrospectiva de pacientes con VIH ingresados en el Hospital General Docente "Enrique Cabrera" en el período comprendido del 1RO de enero de 2007 hasta 31 de diciembre de 2013. La muestra estuvo constituida por 86 casos. Resultados: El número de pacientes se incrementó por años, los casos masculinos constituyeron 79%, los grupos de edad más frecuentes 21 a 30 y 41 a 50 años. Las adenopatías generalizadas fue el hallazgo al examen físico más frecuente. Predominó el conteo de T CD4 menor de 200 células/mm3. Las patologías respiratorias constituyeron 25% de las causas de ingreso. Se realizó el diagnostico hospitalario en 36% de los casos de los cuales el 77% eran diagnósticos tardíos de la enfermedad. Conclusiones: Los pacientes con VIH constituyen una población joven que ingresa cada vez más a nivel secundario hospitalario, con características propias de esta enfermedad y patologías que ponen en riesgo su vida.

ABSTRACT Introduction: The care of patients with Human Immunodeficiency Virus is currently carried out in a decentralized way in Cuba. The number of patients with HIV admitted to general hospitals is increasing. Objective: To determine the clinical characteristics of patients with HIV admitted to Enrique Cabrera General Teaching Hospital. Material and Methods: A descriptive retrospective study was carried out in patients with HIV admitted to Enrique Cabrera General Teaching Hospital from January 1st, 2007 to December 31st, 2013. The sample consisted of 86 cases. Results: The number of patients increased per year, male cases constituted 79 %, the most frequent age groups were from 21 to 30 years and from 41 to 50 years. Generalized adenopathies were the most frequent findings on physical examination. CD4 T- cell counts below 200 cells/mm3 predominated in the study. Respiratory pathologies constituted 25 % of the causes of admission. Hospital diagnosis was carried out in 36 % of the cases, 77 % of which had late diagnoses of HIV. Conclusions: HIV patients constitute a young population that is admitted more and more to secondary level hospitals. They present own characteristics of the disease and pathologies that put their lives at risk.

Proviral Quasispecies Diversity Is Not Associated With Virologic Breakthrough or CD4+ T Cell Loss in HIV-1 Elite Controllers.

Elite controllers (EC) are able to control HIV-1 replication to extremely low levels (<50 HIV-1 RNA copies/mL) in the absence of antiretroviral therapy. However, some EC experience CD4+ T cell loss and/or lose their ability to control HIV-1 over the course of infection. High levels of HIV-1 env proviral diversity, activated T cells and proinflammatory cytokines were pointed out as relevant biomarkers for detection of EC at risk of virologic/immunologic progression. The aim of this study was to assess the importance of proviral diversity as a prognostic marker of virologic and/or immunologic progression in EC. To this end, we analyzed plasma viremia, total HIV DNA levels, T cells dynamics, and activation/inflammatory biomarkers in EC with low (ECLD = 4) and high (ECHD = 6) HIV-1 env diversity. None of ECLD and ECHD subjects displayed evidence of immunologic progression (decrease in absolute and percentage of CD4+ T cells) and only one ECHD subject presented virologic progression (≥2 consecutive viral loads measurements above the detection limit) 2-5 years after determination of proviral env diversity. Despite differences in proviral genetic diversity, the ECLD and ECHD subgroups displayed comparable levels of total cell-associated HIV DNA, activated CD8+ T (CD38+HLA-DR+) cells and plasmatic inflammatory biomarkers (IP-10, IL-18, RANTES, PDGF-AA, and CTACK). These results indicate that the genetic diversity of the HIV-1 proviral reservoir is not a surrogate marker of residual viral replication, immune activation or inflammation, nor an accurate biomarker for the prediction of virologic breakthrough or CD4+ T cells loss in EC.

T-Cell-Driven Inflammation as a Mediator of the Gut-Brain Axis Involved in Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder affecting mainly the dopaminergic neurons of the nigrostriatal pathway, a neuronal circuit involved in the control of movements, thereby the main manifestations correspond to motor impairments. The major molecular hallmark of this disease corresponds to the presence of pathological protein inclusions called Lewy bodies in the midbrain of patients, which have been extensively associated with neurotoxic effects. Importantly, different research groups have demonstrated that CD4+ T-cells infiltrate into the substantia nigra of PD patients and animal models. Moreover, several studies have consistently demonstrated that T-cell deficiency results in a strong attenuation of dopaminergic neurodegeneration in animal models of PD, thus indicating a key role of adaptive immunity in the neurodegenerative process. Recent evidence has shown that CD4+ T-cell response involved in PD patients is directed to oxidised forms of α-synuclein, one of the main constituents of Lewy bodies. On the other hand, most PD patients present a number of non-motor manifestations. Among non-motor manifestations, gastrointestinal dysfunctions result especially important as potential early biomarkers of PD, since they are ubiquitously found among confirmed patients and occur much earlier than motor symptoms. These gastrointestinal dysfunctions include constipation and inflammation of the gut mucosa and the most distinctive pathologic features associated are the loss of neurons of the enteric nervous system and the generation of Lewy bodies in the gut. Moreover, emerging evidence has recently shown a pivotal role of gut microbiota in triggering the development of PD in genetically predisposed individuals. Of note, PD has been positively correlated with inflammatory bowel diseases, a group of disorders involving a T-cell driven inflammation of gut mucosa, which is strongly dependent in the composition of gut microbiota. Here we raised the hypothesis that T-cell driven inflammation, which mediates dopaminergic neurodegeneration in PD, is triggered in the gut mucosa. Accordingly, we discuss how structural components of commensal bacteria or how different mediators produced by gut-microbiota, including short-chain fatty acids and dopamine, may affect the behaviour of T-cells, triggering the development of T-cell responses against Lewy bodies, initially confined to the gut mucosa but later extended to the brain.

Lower High-Density Lipoproteins Levels During Human Immunodeficiency Virus Type 1 Infection Are Associated With Increased Inflammatory Markers and Disease Progression.

INTRODUCTION: High-density lipoproteins (HDL) are responsible for the efflux and transport of cholesterol from peripheral tissues to the liver. In addition, HDL can modulate various immunological mechanisms, including the inflammatory response. Inflammasomes are multiprotein complexes that have been reported to be activated during human immunodeficiency virus type 1 (HIV-1) infection, thus contributing to immune hyperactivation, which is the main pathogenic mechanism of HIV-1 progression. However, the relationship between HDL and inflammasomes in the context of HIV-1 infection is unclear. Therefore, this research aims to explore the association between HDL and the components of the inflammatory response during HIV-1 infection. METHODOLOGY: A cross-sectional study, including 36 HIV-1-infected individuals without antiretroviral treatment and 36 healthy controls matched by sex and age, was conducted. Viral load, CD4+ T-cell counts, serum HDL, and C-reactive protein (CRP) were quantified. Serum cytokine levels, including IL-1ß, IL-6, and IL-18, were assessed by ELISA. The inflammasome-related genes in peripheral blood mononuclear cells were determined by quantitative real-time PCR. RESULTS: HIV-1-infected individuals showed a significant decrease in HDL levels, particularly those subjects with higher viral load and lower CD4+ T-cell counts. Moreover, upregulation of inflammasome-related genes (NLRP3, AIM2, ASC, IL-1ß, and IL-18) was observed, notably in those HIV-1-infected individuals with higher viral loads (above 5,000 copies/mL). Serum levels of IL-6 and CRP were also elevated in HIV-1-infected individuals. Significant negative correlations between HDL and the mRNA of NLRP3, AIM2, ASC, IL-1ß, and IL-18, as well as viral load and CRP were observed in HIV-1-infected individuals. Likewise, a significant positive correlation between HDL and CD4+ T-cell counts was found. CONCLUSION: In summary, our results indicate that HDL might modulate the expression of several key components of the inflammasomes during HIV-1 infection, suggesting a novel role of HDL in modifying the inflammatory state and consequently, the progression of HIV-1 infection.

Sporothrix schenckii Immunization, but Not Infection, Induces Protective Th17 Responses Mediated by Circulating Memory CD4+ T Cells.

Sporotrichosis is a chronic subcutaneous mycosis caused by the Sporothrix schenckii species complex and it is considered an emerging opportunistic infection in countries with tropical and subtropical climates. The host's immune response has a main role in the development of this disease. However, it is unknown the features of the memory cellular immune response that could protect against the infection. Our results show that i.d. immunization in the ears of mice with inactivated S. schenckii conidia (iC) combined with the cholera toxin (CT) induces a cellular immune response mediated by circulating memory CD4+ T cells, which mainly produce interleukin 17 (IL-17). These cells mediate a strong delayed-type hypersensitivity (DTH) reaction. Systemic and local protection against S. schenckii was mediated by circulating CD4+ T cells. In contrast, the infection induces a potent immune response in the skin mediated by CD4+ T cells, which have an effector phenotype that preferentially produce interferon gamma (IFN-γ) and mediate a transitory DTH reaction. Our findings prove the potential value of the CT as a potent skin adjuvant when combined with fungal antigens, and they also have important implications for our better understanding of the differences between the memory immune response induced by the skin immunization and those induced by the infection; this knowledge enhances our understanding of how a protective immune response against a S. schenckii infection is developed.

Propionibacterium acnes Enhances the Immunogenicity of HIVBr18 Human Immunodeficiency Virus-1 Vaccine.

Immunization of BALB/c mice with HIVBr18, a DNA vaccine containing 18 CD4+ T cell epitopes from human immunodeficiency virus (HIV), induced specific CD4+ and CD8+ T cell responses in a broad, polyfunctional and persistent manner. With the aim of increasing the immunogenicity of this vaccine, the effect of Propionibacterium acnes as an adjuvant was evaluated. The adjuvant effects of this bacterium have been extensively demonstrated in both experimental and clinical settings. Herein, administration of two doses of HIVBr18, in the presence of P. acnes, increased the proliferation of HIV-1-specific CD4+ and CD8+ T lymphocytes, the polyfunctional profile of CD4+ T cells, the production of IFN-γ, and the number of recognized vaccine-encoded peptides. One of the bacterial components responsible for most of the adjuvant effects observed was a soluble polysaccharide extracted from the P. acnes cell wall. Furthermore, within 10 weeks after immunization, the proliferation of specific T cells and production of IFN-γ were maintained when the whole bacterium was administered, demonstrating a greater effect on the longevity of the immune response by P. acnes. Even with fewer immunization doses, P. acnes was found to be a potent adjuvant capable of potentiating the effects of the HIVBr18 vaccine. Therefore, P. acnes may be a potential adjuvant to aid this vaccine in inducing immunity or for therapeutic use.