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CD4 + T cells migrate throughout the body and form immune synapses to carry out their functions. Both of these actions require dynamic actin structures, which are disrupted by HIV proteins. Our study suggests that a key HIV protein, Nef, might disrupt a vital internal cellular machinery that helps immune cells move and function properly. Our microscopic and proteomics studies suggest a new model in which Nef inhibits a large protein complex at the front of migrating T cells. Restoring this cytoskeletal dysfunction may be key to restoring CD4 + T-cell survival and function, which may improve adaptive immune responses during HIV infection.

Current Influenza A virus (IAV) vaccines, which primarily aim to generate neutralizing antibodies against the major surface proteins of specific IAV strains predicted to circulate during the annual ‘flu’ season, are suboptimal and are characterized by relatively low annual vaccine efficacy. One approach to improve protection is for vaccines to also target the priming of virus-specific T cells that can protect against IAV even in the absence of preexisting neutralizing antibodies. CD4 T cells represent a particularly attractive target as they help to promote responses by other innate and adaptive lymphocyte populations and can also directly mediate potent effector functions. Studies in murine models of IAV infection have been instrumental in moving this goal forward. Here, we will review these findings, focusing on distinct subsets of CD4 T cell effectors that have been shown to impact outcomes. This body of work suggests that a major challenge for next-generation vaccines will be to prime a CD4 T cell population with the same spectrum of functional diversity generated by IAV infection. This goal is encapsulated well by the motto ‘ex pluribus unum’: that an optimal CD4 T cell response comprises many individual specialized subsets responding together.

Autoimmune uveitis (AU), an inflammatory non-infectious process of the vascular layer of the eye, can lead to visual impairment and, in the absence of a timely diagnosis and suitable therapy, can even result in total blindness. The majority of AU cases are idiopathic, whereas fewer than 20 % are associated with systemic diseases. The clinical severity of AU depends on whether the anterior, intermediate, or posterior part of the uvea is involved and may range from almost asymptomatic to rapidly sight-threatening forms. Race, genetic background, and environmental factors can also influence the clinical picture. The pathogenetic mechanism of AU is still poorly defined, given its remarkable heterogeneity and the many discrepancies between experimental and human uveitis. Even so, the onset of AU is thought to be related to an aberrant T cell-mediated immune response, triggered by inflammation and directed against retinal or cross-reactive antigens. B cells may also play a role in uveal antigen presentation and in the subsequent activation of T cells. The management of AU remains a challenge for clinicians, especially because of the paucity of randomized clinical trials that have systematically evaluated the effectiveness of different drugs. In addition to topical treatment, several different therapeutic options are available, although a standardized regimen is thus far lacking. Current guidelines recommend corticosteroids as the first-line therapy for patients with active AU. Immunosuppressive drugs may be subsequently required to treat steroid-resistant AU and for steroid-sparing purposes. The recent introduction of biological agents, such as those targeting tumor necrosis factor-α, is expected to remarkably increase the percentages of responders and to prevent irreversible sight impairment. This paper reviews the clinical features of AU and its crucial pathogenetic targets in relation to the current therapeutic perspectives. Also, the largest clinical trials conducted in the last 12 years for the treatment of AU are summarized and critically discussed.

Induced pluripotent stem cell (iPSC)-derived T cells offer a renewable source for off-the-shelf immunotherapy. With the advent of the artificial thymic organoid (ATO) method, the in vitro differentiation of CD4 T cells from iPSCs has also become feasible. CD4⁺ T cells have shown superior longevity, resistance to exhaustion, and helper functions in primary settings, but whether iPSC-derived CD4⁺ T cells retain these features remains unclear. In this study, CD4⁺ T cells were differentiated from human iPSCs using the ATO system. Primary T cells served as controls to evaluate the phenotypic and activation features of iPSC-derived CD4⁺ and CD8⁺ T cells. To assess antitumor function, we generated CD19-BBζ CAR-iPSC-T cells and employed a hematologic malignancy model using NALM6 acute lymphoblastic leukemia (ALL) cells. Both short-term and long-term cytotoxicity assays were conducted to compare iPSC-derived CD4⁺ and CD8⁺ T cells in terms of killing efficiency, cytokine secretion, persistence, exhaustion phenotype, and proliferative capacity. The helper function of iPSC-derived CD4⁺ T cells toward CD8⁺ T cells was further evaluated by Ki-67 staining and proliferation assays. Statistical analyses were performed using GraphPad Prism. Our study demonstrated that iPSC-derived CD4⁺ T cells exhibited both helper- and cytotoxic-like features. Compared with iPSC-derived CD8⁺ T cells or CD4⁺/CD8⁺ mixtures, iPSC-derived CD4⁺ T cells showed superior proliferation, cytokine secretion, and sustained cytotoxicity following CAR transduction. They also promoted the expansion of iPSC-derived CD8⁺ T cells and displayed helper-like functions with increased resistance to exhaustion. Although not identical to primary CD4⁺ T cells, iPSC-derived CD4⁺ T cells recapitulated key functional advantages, especially sustained antitumor activity, supporting their value as a renewable, off-the-shelf source for next-generation CAR-T therapies.

Background Autoimmune disease-associated variants are preferentially found in regulatory regions in immune cells, particularly CD4 + T cells. Linking such regulatory regions to gene promoters in disease-relevant cell contexts facilitates identification of candidate disease genes. Results Within 4 h, activation of CD4 + T cells invokes changes in histone modifications and enhancer RNA transcription that correspond to altered expression of the interacting genes identified by promoter capture Hi-C. By integrating promoter capture Hi-C data with genetic associations for five autoimmune diseases, we prioritised 245 candidate genes with a median distance from peak signal to prioritised gene of 153 kb. Just under half (108/245) prioritised genes related to activation-sensitive interactions. This included IL2RA , where allele-specific expression analyses were consistent with its interaction-mediated regulation, illustrating the utility of the approach. Conclusions Our systematic experimental framework offers an alternative approach to candidate causal gene identification for variants with cell state-specific functional effects, with achievable sample sizes.

Background Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) control lung cancer in patients with EGFR mutations, but resistance develops over time. Patients with high levels of genetic mutations rapidly acquire EGFR-TKI resistance. T cell immunity recognizes gene mutation products as neoantigens that effectively suppress mutation levels by eliminating clones with more mutations; this process is known as cancer immune editing. Therefore, EGFR-TKI-resistant clones may be less likely to form in cases with active antitumor T cell immune responses. However, the relationship between EGFR-TKI resistance and antitumor T cell response in patients with EGFR mutation remains unclear. To determine the relationship between the duration of EGFR-TKI resistance acquisition and antitumor T cell immunity, and the effect of EGFR-TKIs on T cell immunity. Methods This prospective observational study enrolled 43 patients who received osimertinib. Blood samples were collected prior to and following 4 weeks of EGFR-TKI administration. Results The median PFS and OS for the 37 patients were 24.8 and 32.9 months, respectively. Patients with higher CXCR3 + CCR4 − CCR6 + CD4 + T cell levels exhibited significantly enhanced PFS ( p  = 0.002) and OS ( p  = 0.0006). Other T cell subsets (Th1, Th2, Th17, and CD8 + ) exhibited no significant correlation with PFS. The percentage of CXCR3 + CCR4 − CCR6 + CD4 + T cells was significantly reduced with tumor volume reduction ( p  < 0.0001). Conclusions T cell immunity affects the time required to acquire resistance after EGFR-TKI treatment. Pretreatment CXCR3 + CCR4 − CCR6 + CD4 + T cell cluster was significantly associated with PFS after osimertinib treatment, likely predicting osimertinib efficacy. Antitumor T cell immunity may be crucial for preventing the acquisition of EGFR-TKI resistance.

Background Alzheimer's disease (AD) is a debilitating neurodegenerative disorder that is difficult to predict and is typically diagnosed only after symptoms manifest. Recently, CD4+ T cell‐derived double‐negative T (DNT) cells have shown strong immuno‐regulatory properties in both in vitro and in vivo neuronal inflammation studies. However, the effectiveness of DNT cells in treating on AD are not yet fully understood. Objective This study's aims were three‐fold, to (1) evaluate the efficacy of CD4+ T cell‐derived DNT cells treatment on AD mice, (2) understand how DNT treatment make changes in different cell types of 5FAD mice, (3) identify the side effects of DNT treatment. Methods We performed tail vein injection of transformed and amplified CD4+ T cell‐derived DNT cells into 5 × FAD mice, while using WT mice and saline injection 5FAD mice as controls. DNT suspensions or NaCl alone were administered to 5 × FAD mice at the 6 months of age. For intravenous injection (n = 10 for both DNT and control injections), 5 × FAD mice were injected with a total of 5 × 106 DNT cells suspended in 200 μL of 0.9% NaCl or 0.9% NaCl alone via the lateral tail vein. Behavioral tests and pathology tests were carried out 30 days after cell transplantation. Results Through qualitative analysis, we identified 6 main themes. DNT from young wild‐type mice enhance the capability of spatial learning and memory in AD mice. DNT cell treatment rejuvenates the microglial function. DNT cell treatment improves the state of oligodendrocytes. DNT cell treatment finetunes the activation of the immune system. DNT cell treatment improves the synaptic plasticity and increases the complexity of neurons. DNT cell treatment reduces the density of amyloid Beta plaques deposition in the cortex and hippocampus of 5 × FAD mice. Discussion The findings from this study reveal that DNT treatment improved spatial memory and learning abilities, reduced Aβ deposition, and enhanced synaptic plasticity, contrasting with previous reports on thymus‐derived DNT cells. Additionally, CD4+ T cell‐derived DNT therapy exhibited anti‐inflammatory effects and modulated microglial function, promoting a neuroprotective environment. Notably, DNT treatment also reduced tau pathology by decreasing levels of abnormally phosphorylated tau. These findings suggest that CD4+ T cell‐derived DNT cells hold therapeutic potential for AD, effectively targeting both Aβ and tau pathologies. We focused on a subset of CD4‐derived double‐negative T (DNT) cells called TCRαβ+NK1.1−CD4−CD8− for treating Alzheimer's disease, and we found their injection can improve cognition of the 5×FAD mouse model. We thus identify DNT cell transplantation as a potential therapeutic approach for future AD treatments.

Single-cell gene expression analysis using sequencing (scRNA-seq) has gained increased attention in the past decades for studying cellular transcriptional programs and their heterogeneity in an unbiased manner, and novel protocols allow the simultaneous measurement of gene expression, T-cell receptor clonality and cell surface protein expression. In this article, we describe the methods to isolate scRNA/TCR-seq-compatible CD4 + T cells from murine tissues, such as skin, spleen, and lymph nodes. We describe the processing of cells and quality control parameters during library preparation, protocols for multiplexing of samples, and strategies for sequencing. Moreover, we describe a step-by-step bioinformatic analysis pipeline from sequencing data generated using these protocols. This includes quality control, preprocessing of sequencing data and demultiplexing of individual samples. We perform quantification of gene expression and extraction of T-cell receptor alpha and beta chain sequences, followed by quality control and doublet detection, and methods for harmonization and integration of datasets. Next, we describe the identification of highly variable genes and dimensionality reduction, clustering and pseudotemporal ordering of data, and we demonstrate how to visualize the results with interactive and reproducible dashboards. We will combine different analytic R-based frameworks such as Bioconductor and Seurat , illustrating how these can be interoperable to optimally analyze scRNA/TCR-seq data of CD4 + T cells from murine tissues.

Immunological non-responders (INR), a subgroup of people living with HIV (PLHIV) who fail to restore CD4 + T cell numbers upon effective antiretroviral treatment, have impaired gut mucosal barrier function and an inferior clinical prognosis compared with immunological responders (IR). The contribution of gut-homing and exhaustion of mucosal T cells to the INR phenotype was previously unknown. Flow cytometry analysis of mononuclear cells from peripheral blood and ileal and colonic lamina propria showed that INR had higher fractions of gut-homing CD4 + T cells in blood compared with IR. In addition, gut-homing cells were more likely to display signs of exhaustion in INR. The increased CD4 + T cell exhaustion in INR was ubiquitous and not restricted to subpopulations defined by activation, differentiation or regulatory T cell markers. In INR, colon CD4 + T cell exhaustion correlated negatively with the fraction of CD4 + T cells in the same compartment, this was not apparent in the ileum. The fraction of exhausted mucosal CD4 + T cells correlated with I-FABP and REG3α, markers of enterocyte damage. We conclude that alterations of gut-homing and exhaustion of T cells may contribute to impaired gut immune and barrier functions associated with immunological non-response in PLHIV.

Antibodies to citrullinated proteins, common in rheumatoid arthritis (RA) patients, are strongly associated to a specific set of HLA-DR alleles including HLA-DRB1*04:01, *04:04, and *01:01. Here, we first demonstrate that autoantibody levels toward the dominant citrullinated B cell epitope from α-enolase are significantly elevated in HLA-DRB1*04:01-positive RA patients. Furthermore, we identified α-enolase-derived T cell epitopes and demonstrated that native and citrullinated versions of several peptides bind with different affinities to HLA-DRB1*04:01, *04:04, and *01:01. The citrulline residues in the eight identified peptides are distributed throughout the entire length of the presented epitopes and more specifically, localized at peptide positions p-2, p2, p4, p6, p7, p10, and p11. Importantly, in contrast to its native version peptide 26 (TSKGLF AAVPSGAS), the HLA-DRB1*04:01-restricted citrullinated peptide Cit26 (TSKGLF AAVPSGAS) elicited significant functional T cell responses in primary cells from RA patients. Comparative analysis of the crystal structures of HLA-DRB1*04:01 in complex with peptide 26 or Cit26 demonstrated that the posttranslational modification did not alter the conformation of the peptide. And since citrullination is the only structural difference between the two complexes, this indicates that the neo-antigen Cit26 is recognized by T cells with high specificity to the citrulline residue.