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Immunological memory is important to protect humans against recurring diseases. Memory CD8 + T cells are required for quick expansion into effector cells but also provide immediate cytotoxicity against their targets. Whereas many functions of the two main cytotoxic subtypes, effector memory CD8 + T cells (T EM ) and central memory CD8 + T cells (T CM ), are well defined, single T EM and T CM cell cytotoxicity has not been quantified. To quantify cytotoxic efficiency of T EM and T CM , we developed a FRET-based single cell fluorescent assay with NALM6 target cells which allows analysis of target cell apoptosis, secondary necrosis following apoptosis, and primary necrosis after T EM - or T CM -target cell contact. Both, single cell and population cytotoxicity assays reveal a higher cytotoxic efficiency of T EM compared to T CM , as quantified by target cell apoptosis and secondary necrosis. Perforin, granzyme B, FasL, but not TRAIL expression are higher in T EM compared to T CM . Higher perforin levels (likely in combination with higher granzyme levels) mediate higher cytotoxic efficiency of T EM compared to T CM . Both, T EM and T CM need the same time to find their targets, however contact time between CTL and target, time to induce apoptosis, and time to induce secondary necrosis are all shorter for T EM . In addition, immune synapse formation in T EM appears to be slightly more efficient than in T CM . Defining and quantifying single T EM and T CM cytotoxicity and the respective mechanisms is important to optimize future subset-based immune therapies.

The host immune response has a prominent role in the progression and outcome of SARS-CoV-2 infection. Lymphopenia has been described as an important feature of SARS-CoV-2 infection and has been associated with severe disease manifestation. Lymphocyte dysregulation and hyper-inflammation have been shown to be associated with a more severe clinical course; however, a T cell subpopulation whose dysfunction correlate with disease progression has yet to be identify. We performed an immuno-phenotypic analysis of T cell sub-populations in peripheral blood from patients affected by different severity of COVID-19 (n=60) and undergoing a different clinical evolution. Clinical severity was established based on a modified WHO score considering both ventilation support and respiratory capacity (PaO2/FiO2 ratio). The ability of circulating cells at baseline to predict the probability of clinical aggravation was explored through multivariate regression analyses. The immuno-phenotypic analysis performed by multi-colour flow cytometry confirmed that patients suffering from severe COVID-19 harboured significantly reduced circulating T cell subsets, especially for CD4 T, Th1, and regulatory T cells. Peripheral T cells also correlated with parameters associated with disease severity, i.e., PaO2/FiO2 ratio and inflammation markers. CD4 T cell subsets showed an important significant association with clinical evolution, with patients presenting markedly decreased regulatory T cells at baseline having a significantly higher risk of aggravation. Importantly, the combination of gender and regulatory T cells allowed distinguishing between improved and worsened patients with an area under the ROC curve (AUC) of 82%. The present study demonstrates the association between CD4 T cell dysregulation and COVID-19 severity and progression. Our results support the importance of analysing baseline regulatory T cell levels, since they were revealed able to predict the clinical worsening during hospitalization. Regulatory T cells assessment soon after hospital admission could thus allow a better clinical stratification and patient management.

The study aimed to explore the underlying immunologic mechanisms and immune-related biomarkers associated with alopecia areata (AA) development. Expression data from the GSE68801 dataset, concerning 60 individuals with alopecia areata (28 patchy-type AA (AAP), 23 alopecia universalis (AU), 9 alopecia totalis (AT)), and 36 normal controls (NC), were analyzed. The study investigated differentially expressed RNAs (DERs), immune infiltration, and immune-related modules. Functional enrichment analysis of overlapping DERs was conducted using DAVID. Additionally, overlapping pathways and genes identified in a co-expression network, along with data from the Comparative Toxicogenomics Database 2019 update, were screened. In total, 1708 lncRNAs and 17,326 mRNAs, along with 427 overlapping DERs among AAP, AU, AT, and NC, were identified. Subsequently, 17 biological processes significantly associated with inflammatory and immune responses, as well as 8 KEGG signaling pathways, including the chemokine and cytokine-cytokine receptor interaction pathway, were enriched. Notable differences in the infiltration of four T cell subtypes - activated CD8 T cells, effector memory CD8 T cells, regulatory T cells, and plasmacytoid dendritic cells - were observed compared to NC. Two modules were found to be significantly linked to disease stage progression and various T cell types. Functional analysis revealed significant enrichment of cytokine-cytokine receptor interaction and the T cell receptor signaling pathway among the genes involved in these modules. Furthermore, CXCL9 and CXCL10 were identified as key nodes associated with the disease. Our study revealed that AA is an autoimmune disease associated with T cells, with CXCL9 and CXCL10 emerging as significant prognostic factors in its development.

Human immunodeficiency virus (HIV) infection remains an important global public health problem. About 40 million people are infected with HIV, and this infection caused about 630,000 deaths in 2022. The hallmark of HIV infection is the depletion of CD4+ T helper lymphocytes (Th cells). There are at least seven different Th subtypes, and not all are the main targets of HIV. Moreover, the effect of the virus in a specific subtype can be completely different from that of the others. Although the most compromised Th subtype in HIV infection is Th17, HIV can induce important dysregulations in other subtypes, such as follicular Th (Tfh) cells and regulatory Th cells (Treg cells or Tregs). Several studies have shown that HIV can induce an increase in the immunosuppressive activity of Tregs without causing a significant reduction in their numbers, at least in the early phase of infection. The increased activity of this Th subtype seems to play an important role in determining the immunodeficiency status of HIV-infected patients, and Tregs may represent a new target for innovative anti-HIV therapies, including the so-called “Kick and Kill” therapeutic method whose goal is the complete elimination of the virus and the healing of HIV infection. In this review, we report the most important findings on the effects of HIV on different CD4+ T cell subtypes, the molecular mechanisms by which the virus impairs the functions of these cells, and the implications for new anti-HIV therapeutic strategies.

The immune response implicated in Coronavirus disease 2019 (COVID-19) pathogenesis remains to be fully understood. The present study aimed to clarify the alterations in CD4+ and CD8+ memory T cells’ compartments in SARS-CoV-2-infected patients, with an emphasis on various comorbidities affecting COVID-19 patients. Peripheral blood samples were collected from 35 COVID-19 patients, 16 recovered individuals, and 25 healthy controls, and analyzed using flow cytometry. Significant alterations were detected in the percentage of CD8+ T cells and effector memory-expressing CD45RA CD8+ T cells (TEMRA) in COVID-19 patients compared to healthy controls. Interestingly, altered percentages of CD4+ T cells, CD8+ T cells, T effector (TEff), T naïve cells (TNs), T central memory (TCM), T effector memory (TEM), T stem cell memory (TSCM), and TEMRA T cells were significantly associated with the disease severity. Male patients had more CD8+ TSCMs and CD4+ TNs cells, while female patients had a significantly higher percentage of effector CD8+CD45RA+ T cells. Moreover, altered percentages of CD8+ TNs and memory CD8+CD45RO+ T cells were detected in diabetic and non-diabetic COVID-19 patients, respectively. In summary, this study identified alterations in memory T cells among COVID-19 patients, revealing a sex bias in the percentage of memory T cells. Moreover, COVID-19 severity and comorbidities have been linked to specific subsets of T memory cells which could be used as therapeutic, diagnostic, and protective targets for severe COVID-19.

Objective The traditional treatment of rheumatoid arthritis (RA) has some side effects. We aimed to explore the effect of metformin treatment on the expression of HMGB1, cytokines, T cell subtypes and the clinical outcomes in RA patients. Methods The present prospective cohort study recruited 124 RA patients (metformin group) who were treated with metformin and conventional therapy (methotrexate, hydroxychloroquine sulfate and sulfasalazine) and 98 RA patients (conventional therapy group) who were only treated with conventional therapy. All subjects were admitted from December 2018 to December 2021 and continuous medication for 90 days. The serum high mobility group box 1 (HMGB1), tumor necrosis factor α (TNF-α), interleukin (IL)-6, IL-1β and C-reactive protein (CRP) levels were measured by enzyme-linked immunosorbent assay (ELISA). Flow cytometric were used to analyze the expression of CD4 + and CD8 + . Demographic and clinical statistics including age, body mass index (BMI), sex, course of disease, erythrocyte sedimentation rate (ESR), rheumatoid factor (RF), visual analogue score (VAS)and disease activity score (DAS)-28 were collected. Results The serum levels of HMGB1, CRP, IL-6, CD4+ expression and CD4+/CD8+ ratio were significantly increased in patients with DAS-28 score ≥ 2.6. The serum HMGB1 and cytokines levels of metformin group declined more quickly during the study time. Pearson’s analysis supported that a positive correlation existed between the HMGB1 and IL-6, TNF-α, CRP, CD4 + , CD4 + /CD8 + ratio, and VAS scores. HMGB1 could be a potential diagnostic biomarker for RA patients in active phase. Serum HMGB1 (95% CI 1.133–1.397, P  < 0.001) was a factor associated with active RA. Conclusion The serum HMGB1 levels were significantly increased in RA patients in active phase. The serum levels of HMGB1 and inflammatory factors and VAS scores were decreased gradually with metformin treatment. HMGB1 might act as a novel therapeutic target for RA.

Multiple sclerosis (MS) is a severe disease of the central nervous system (CNS) characterized by autoimmune inflammation and neurodegeneration. Historically, damage to the CNS was thought to be mediated predominantly by activated pro-inflammatory T cells. B cell involvement in the pathogenesis of MS was solely attributed to autoantibody production. The first clues for the involvement of antibody-independent B cell functions in MS pathology came from positive results in clinical trials of the B cell-depleting treatment rituximab in patients with relapsing-remitting (RR) MS. The survival of antibody-secreting plasma cells and decrease in T cell numbers indicated the importance of other B cell functions in MS such as antigen presentation, costimulation, and cytokine production. Rituximab provided us with an example of how clinical trials can lead to new research opportunities concerning B cell biology. Moreover, analysis of the antibody-independent B cell functions in MS has gained interest since these trials. Limited information is present on the effects of current immunomodulatory therapies on B cell functions, although effects of both first-line (interferon, glatiramer acetate, dimethyl fumarate, and teriflunomide), second-line (fingolimod, natalizumab), and even third-line (monoclonal antibody therapies) treatments on B cell subtype distribution, expression of functional surface markers, and secretion of different cytokines by B cells have been studied to some extent. In this review, we summarize the effects of different MS-related treatments on B cell functions that have been described up to now in order to find new research opportunities and contribute to the understanding of the pathogenesis of MS.

To evaluate the benefits of SARS-CoV-2 vaccination in cancer patients it is relevant to understand the adaptive immune response elicited after vaccination. Patients affected by hematologic malignancies are frequently immune-compromised and show a decreased seroconversion rate compared to other cancer patients or controls. Therefore, vaccine-induced cellular immune responses in these patients might have an important protective role and need a detailed evaluation. Certain T cell subtypes (CD4, CD8, Tfh, γδT), including cell functionality as indicated by cytokine secretion (IFN, TNF) and expression of activation markers (CD69, CD154) were assessed multi-parameter flow cytometry in hematologic malignancy patients (N=12) and healthy controls (N=12) after a second SARS-CoV-2 vaccine dose. The PBMC of post-vaccination samples were stimulated with a spike-peptide pool (S-Peptides) of SARS-CoV-2, with CD3/CD28, with a pool of peptides from the cytomegalovirus, Epstein-Barr virus and influenza A virus (CEF-Peptides) or left unstimulated. Furthermore, the concentration of spike-specific antibodies has been analyzed in patients. Our results indicate that hematologic malignancy patients developed a robust cellular immune response to SARS-CoV-2 vaccination comparable to that of healthy controls, and for certain T cell subtypes even higher. The most reactive T cells to SARS-CoV-2 spike peptides belonged to the CD4 and Tfh cell compartment, being median (IQR), 3.39 (1.41-5.92) and 2.12 (0.55-4.14) as a percentage of IFN- and TNF-producing Tfh cells in patients. In this regard, the immunomodulatory treatment of patients before the vaccination period seems important as it was strongly associated with a higher percentage of activated CD4 and Tfh cells. SARS-CoV-2- and CEF-specific T cell responses significantly correlated with each other. Compared to lymphoma patients, myeloma patients had an increased percentage of SARS-CoV-2-specific Tfh cells. T-SNE analysis revealed higher frequencies of γδT cells in patients compared to controls, especially in myeloma patients. In general, after vaccination, SARS-CoV-2-specific T cells were also detectable in patients without seroconversion. Hematologic malignancy patients are capable of developing a SARS-CoV-2-specific CD4 and Tfh cellular immune response after vaccination, and certain immunomodulatory therapies in the period before vaccination might increase the antigen-specific immune response. A proper response to recall antigens (e.g., CEF-Peptides) reflects immune cellular functionality and might be predictive for generating a newly induced antigen-specific immune response as is expected after SARS-CoV-2 vaccination.

Atopic dermatitis (AD) presents as a prevalent chronic, relapsing, inflammatory skin condition. While dupilumab has proven effective in treating moderate-to-severe AD, some patients still experience unsatisfactory outcomes with this therapy in clinical settings. Patients with AD receiving dupilumab were selected for inclusion in the present study for prospective observations. Over an 8-week period, the patients underwent monitoring and changes in serum biomarkers and circulating T helper (Th) cell levels were analyzed using questionnaires, ELISA and flow cytometry. The Scoring Atopic Dermatitis (SCORAD), Objective-SCORAD, Itch Numeric Rating Scale (NRS), Dermatology Life Quality Index, Patient Oriented Eczema measure and Atopic Dermatitis Control Tools scores in patients with AD significantly decreased at week 8 compared with those before treatment (P<0.05). Moderate positive correlations were demonstrated between serum thymus and activation-regulated chemokine (TARC) and human β-defensin 2 levels and Eczema Area and Severity Index (EASI) and SCORAD scores (P<0.05). A weak negative correlation was shown between serum IgE against Staphylococcus aureus enterotoxin A level and the EASI and SCORAD scores, although these were not statistically significant (P>0.05). There was a notable increase in the proportion of Th2 cells in peripheral blood at week 2 (P<0.05). The proportion of Th22 cells in the peripheral blood was weakly correlated with the NRS score (P>0.05). Patients were categorized into rapid or slow groups depending on whether they achieved EASI-75 scores by week 8. The proportion of Th17 cells in peripheral blood in the rapid group at week 8 of treatment was lower than that compared with the slow group at week 2 (P<0.05). The SCORAD scores of the rapid group were significantly lower compared with those of the slow group at week 8 of treatment (P<0.05). The conventional dupilumab treatment regimen led to a marked remission in patients with exogenous AD after 8 weeks of therapy. Significant correlations were observed between serum TARC levels and clinical disease scores (P<0.05), which changed notably during treatment and remained valuable for monitoring disease progression at follow-up. Additionally, the elevated ratio of Th17 cells in peripheral blood at week 2 of treatment showed potential for predicting the attainment of EASI-75 by week 8 after treatment.