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•Mice were vaccinated with BCG for 21 or 120 days before challenged with Mtb.•Mice challenged 120 days after BCG vaccination displayed improved control of Mtb.•BCG-mediated control of Mtb correlates with the IL-17 response and is independent of the magnitude of the IFN-γ response in the lung.•Long-lasting control of Mtb correlates with the accumulation of CD4+ T cells producing IL-17, TNF and IL-2. Mycobacterium bovis Bacille Calmette-Guerin (BCG) is the only vaccine in use to prevent Mycobacterium tuberculosis (Mtb) infection. Here we analyzed the protective efficacy of BCG against Mtb challenges 21 or 120 days after vaccination. Only after 120 days post-vaccination were mice able to efficiently induce early Mtb growth arrest and maintain long-lasting control of Mtb. This protection correlated with the accumulation of CD4+ T cells expressing IL-17+TNF+IL-2+. In contrast, mice challenged with Mtb 21 days after BCG vaccination exhibited only a mild and transient protection, associated with the accumulation of CD4+ T cells that were mostly IFN-γ+TNF+ and to a lesser extent IFN-γ+TNF+IL-2+. These data suggest that the memory response generated by BCG vaccination is functionally distinct depending upon the temporal proximity to BCG vaccination. Understanding how these responses are generated and maintained is critical for the development of novel vaccination strategies against tuberculosis.

CD4+T cells play a notable role in immune protection at different stages of life. During aging, the interaction between the body's internal and external environment and CD4+T cells results in a series of changes in the CD4+T cells pool making it involved in immunosenescence. Many studies have extensively examined the subsets and functionality of CD4+T cells within the immune system, highlighted their pivotal role in disease pathogenesis, progression, and therapeutic interventions. However, the underlying mechanism of CD4+T cells senescence and its intricate association with diseases remains to be elucidated and comprehensively understood. By summarizing the immunosenescent progress and network of CD4+T cell subsets, we reveal the crucial role of CD4+T cells in the occurrence and development of age‐related diseases. Furthermore, we provide new insights and theoretical foundations for diseases targeting CD4+T cell subsets aging as a treatment focus, offering novel approaches for therapy, especially in infections, cancers, autoimmune diseases, and other diseases in the elderly. CD4+T cells play a notable role in immune protection at different stages of life. During aging, the interaction between the body's internal and external environment and CD4+T cells, results in a series of changes in the CD4+T cells pool making it involved in immunosenescence. CD4+T cells subsets aging as a treatment focus, offering novel approaches for therapy, especially in infections, cancers, autoimmune diseases, and other diseases in the elderly.

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.

Osteoclasts (OCs) and dendritic cells (DCs) induce expansion and functional activation of NK and T cells. When comparing OCs with DC-induced activation in NK cells, OCs induced significantly higher cell expansion and functional activation of NK cells as compared to DCs, either from healthy individuals or those obtained from cancer patients. However, no differences could be seen in the levels of cell expansion and functional activation in T cells activated by OCs or DCs, either from healthy individuals or those from cancer patients. OCs selectively expanded and activated CD8 + T cells, whereas DCs expanded and activated CD4 + T cells. In addition, both allogeneic and autologous OCs induced similar levels of cell expansion and functional activation of NK and T cells. Together, these findings highlighted the essential roles of OCs in expanding and activating the cytotoxic effectors of NK, and CD8 + T cells, and demonstrated several differences when compared to the effect of DCs.

Pediatric obesity-related asthma is characterized by non-atopic T helper 1 (Th1) inflammation and steroid resistance. CDC42 upregulation in CD4 + T cells underlies Th1 inflammation but the CD4 + T cell subtype(s) with CDC42 upregulation and their contribution to steroid resistance are not known. Compared to healthy-weight asthma, obesity-alone and healthy-weight controls, single-cell transcriptomics of obese asthma CD4 + T cells revealed CDC42 upregulation in 3 clusters comprised of naïve and central memory T cells, which differed from the cluster enriched for Th1 responses that was comprised of effector T cells. NR3C1 , coding for the glucocorticoid receptor, was downregulated, while genes coding for NLRP3 inflammasome were upregulated, in clusters with CDC42 upregulation and Th1 responses. Conserved genes in these clusters correlated with pulmonary function deficits in obese asthma. These findings suggest that several distinct CD4 + T cell subtypes are programmed in obese asthma for CDC42 upregulation, Th1 inflammation, and steroid resistance, and together contribute to the obese asthma phenotype.

With increasing research on the gut microbiota (GM), there is growing evidence suggesting that GM may influence the risk of knee osteoarthritis (KOA) by modulating immune cell activity. However, the causal relationship between GM, immune cells, and KOA has not been thoroughly investigated. This study aimed to investigate the causal effect of GM on KOA and to identify immune cell mechanisms that may play a mediating role. A bidirectional two-sample univariable Mendelian randomization (UVMR) analysis was conducted to assess the association between GM and KOA. Additionally, mediation analyses were performed to identify critical mediators in the association between GM and KOA, assessing the causal relationship between the two conditions and potential immune cell mediators. UVMR analyses revealed a causal relationship between 20 GM and KOA. Reverse MR analysis revealed that KOA affected the abundance of 12 GM. Mediation analysis identified that CCR7 on naive CD4+, CD4+ on CD39+ activated Tregs mediated the causal effect of GM on KOA (indirect effect: β = 0.049; indirect effect: β =  − 0.047). Furthermore, GM was found to be a significant contributor to the risk of KOA. Specifically, Firmicutes A was associated with increased risk of KOA by increasing CCR7 on naive CD4+ (OR = 1.480; P  = 0.006; FDR = 0.039). In contrast, Rhodanobacter was protective against KOA by modulating CD4+ on CD39+ activated Tregs (OR = 0.780; P  = 0.046; FDR = 0.048). These findings provide a rationale for potential new prevention strategies for KOA.

Background Post-COVID-19 respiratory sequelae often involve lung damage, which is called residual lung abnormalities, and potentially lead to chronic respiratory issues. The adaptive immune response, involving T-cells and B-cells, plays a critical role in pathogen control, inflammation, and tissue repair. However, the link between immune dysregulation and the development of residual lung abnormalities remains unclear. Methods 109 patients discharged with residual lung abnormalities after a critical COVID-19 were followed for 12 months and divided as full recovery patients (FRG, n  = 88) and persistent lung abnormalities (PLAG, n  = 21). Cell profiling analysis was done using flow cytometry at 24 h of not antigen-specific in vitro stimulation. Plasma or supernatant levels of IFN-g, IL-4, IL-10, IgM, and IgG were assessed, and 10 patients (5 FRG, 5 PLAG) were randomly selected for detailed immune cell phenotyping and functional analysis of peripheral blood mononuclear cells using flow cytometry. Results Compared to the FRG group, PLAG exhibited an increase of unswitched ( p  = 0.0159) and decreased double-negative activated B-cells ( p  = 0.0317), systemic IL-10 levels were lower, displayed reduced frequency of total B-cells, and impaired spontaneous IgM ( p  = 0.0357) and IgG ( p  = 0.0079) release in culture. Regarding T-cells, PLAG patients showed a reduction in effector memory CD4 + cells ( p  = 0.0159) and an increase in CD4 + TEMRA cells ( p  = 0.0079) following in vitro stimulation. Notably, the PLAG group also exhibited higher frequencies of central memory CD4 + Th2 (GATA3+) T-cells in response to activation than the FRG group ( p  = 0.0079). Conclusions Patients with residual lung abnormalities 12 months post-critical COVID-19 exhibit impaired B-cell function, increased unswitched B-cells, and higher frequencies of CD4 + TEMRA T-cells following in vitro activation. These immune imbalances may contribute to ongoing lung dysfunction and warrant further investigation as a potential mechanism in residual lung abnormalities. Larger studies are necessary to confirm these findings.

Cytotoxic CD4+ T cells (CD4 CTL) are terminally differentiated T helper cells that contribute to autoimmune diseases, such as multiple sclerosis. We developed a novel triple co-culture transwell assay to study mutual interactions between CD4 CTL, conventional TH cells, and regulatory T cells (Tregs) simultaneously. We show that, while CD4 CTL are resistant to suppression by Tregs in vitro, the conditioned medium of CD4 CTL accentuates the suppressive phenotype of Tregs by upregulating IL-10, Granzyme B, CTLA-4, and PD-1. We demonstrate that CD4 CTL conditioned medium skews memory TH cells to a TH17 phenotype, suggesting that the CD4 CTL induce bystander polarization. In our triple co-culture assay, the CD4 CTL secretome promotes the proliferation of TH cells, even in the presence of Tregs. However, when cell−cell contact is established between CD4 CTL and TH cells, the proliferation of TH cells is no longer increased and Treg-mediated suppression is restored. Taken together, our results suggest that when TH cells acquire cytotoxic properties, these Treg-resistant CD4 CTL affect the proliferation and phenotype of conventional TH cells in their vicinity. By creating such a pro-inflammatory microenvironment, CD4 CTL may favor their own persistence and expansion, and that of other potentially pathogenic TH cells, thereby contributing to pathogenic responses in autoimmune disorders.

Background CNS infection by HIV-1 contributes to neuroinflammation, cognitive impairments, and the establishment of viral reservoirs. Although HIV-1 is known to enter the brain early in infection via “Trojan horse” leukocytes, including infected monocytes and CD4⁺ T cells, the specific cellular phenotypes facilitating this process during acute infection remain incompletely characterized. Objective This study aims to characterize the roles of brain lymphocytes during acute infection and primary CD4 + T cell phenotypes seeding the SIV to the CNS. Methods scRNA-seq was performed on brain and blood cells of three acutely SIV-infected rhesus macaques. The transcriptomic data were analyzed using bioinformatics approaches and validated through in vitro co-culture assays and re-analysis of a publicly available scRNA-seq dataset. Results scRNA-seq of brain and blood immune cells from acutely SIV-infected rhesus macaques revealed an expansion of proliferating CD4⁺ cytotoxic T lymphocytes (CTLs) in the blood, characterized by high CD4, CCR5, and adhesion molecule expression, indicating strong potential for CNS infiltration. In the brain, CD4⁺ CTLs, tissue-resident memory cells, and a unique Myeloid–T cell cluster were enriched for SIV⁺ cells. Integration of brain and blood data revealed transcriptomic maturation of CD4⁺ CTLs upon brain entry. To validate the biological relevance of the Myeloid–T cluster, we used a macrophage–T cell co-culture system, which reproduced similar dual-marker expression and identified chemokines (e.g., CCL3, CCL4) as potential markers of T cell–myeloid cell interaction. Conclusion Our findings suggest that CD4⁺ cytotoxic-like T cells represent a key lymphocyte subset responsible for initiating SIV entry into the brain and triggering neuroinflammatory processes. Furthermore, interactions between infiltrating lymphocytes and brain-resident myeloid cells, potentially through chemokine signaling, may facilitate viral propagation within the CNS.

Cutaneous T-cell lymphomas (CTCLs), particularly Mycosis fungoides (MF), frequently exhibit deletions and reduced expression of HNRNPK in CD4 + T cells. To enable in vivo studies, we developed a conditional Hnrnpk knockout mouse that thrives, facilitating the investigation of HNRNPK ’s role in CTCL onset. We generated mice with a floxed Hnrnpk allele, then crossbred them with Cd4CreER T 2 mice to generate Hnrnpk flox Cd4CreER T 2 mice, all in BL6 background. PCR confirmed the targeted deletion of Hnrnpk in CD4 + T cells after tamoxifen i.p. injection. Skin allergic reactions were induced with oxazolone, and Cre was activated in skin-infiltrating CD4 + T cells using tamoxifen topically after the first allergic skin reaction. The mice exhibited no immediately obvious phenotype. Flow cytometry and histopathological analysis were conducted on blood and skin samples collected throughout the experiment. Following 20 weeks of sustained allergic reactions, inflammation persisted over 20 weeks after challenges ceased, demonstrating early CTCL characteristics such as chronic skin inflammation, CD3 + CD4 + T cell infiltration, and stable peripheral blood parameters. This mouse model provides experimental access to the complex microenvironment and immune responses involved in early inflammatory stages, providing opportunities for further research into the role of HNRNPK in CTCL and the development of effective therapeutic interventions for this challenging malignancy.