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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.

CD4(+) T-cells have been shown to play a central role in immune control of infection with Plasmodium parasites. At the erythrocytic stage of infection, IFN-γ production by CD4(+) T-cells and CD4(+) T-cell help for the B-cell response are required for control and elimination of infected red blood cells. CD4(+) T-cells are also important for controlling Plasmodium pre-erythrocytic stages through the activation of parasite-specific CD8(+) T-cells. However, excessive inflammatory responses triggered by the infection have been shown to drive pathology. Early classical experiments demonstrated a biphasic CD4(+) T-cell response against erythrocytic stages in mice, in which T helper (Th)1 and antibody-helper CD4(+) T-cells appear sequentially during a primary infection. While IFN-γ-producing Th1 cells do play a role in controlling acute infections, and they contribute to acute erythrocytic-stage pathology, it became apparent that a classical Th2 response producing IL-4 is not a critical feature of the CD4(+) T-cell response during the chronic phase of infection. Rather, effective CD4(+) T-cell help for B-cells, which can occur in the absence of IL-4, is required to control chronic parasitemia. IL-10, important to counterbalance inflammation and associated with protection from inflammatory-mediated severe malaria in both humans and experimental models, was originally considered be produced by CD4(+) Th2 cells during infection. We review the interpretations of CD4(+) T-cell responses during Plasmodium infection, proposed under the original Th1/Th2 paradigm, in light of more recent advances, including the identification of multifunctional T-cells such as Th1 cells co-expressing IFN-γ and IL-10, the identification of follicular helper T-cells (Tfh) as the predominant CD4(+) T helper subset for B-cells, and the recognition of inherent plasticity in the fates of different CD4(+) T-cells.

The main obstacle to cure HIV-1 is the latent reservoir. Antiretroviral therapy effectively controls viral replication, however, it does not eradicate the latent reservoir. Latent CD4 + T cells are extremely rare in HIV-1 infected patients, making primary CD4 + T cell models of HIV-1 latency key to understanding latency and thus finding a cure. In recent years several primary CD4 + T cell models of HIV-1 latency were developed to study the underlying mechanism of establishing, maintaining and reversing HIV-1 latency. In the search of biomarkers, primary CD4 + T cell models of HIV-1 latency were used for bulk and single-cell transcriptomics. A wealth of information was generated from transcriptome analyses of different primary CD4 + T cell models of HIV-1 latency using latently- and reactivated HIV-1 infected primary CD4 + T cells. Here, we performed a pooled data-analysis comparing the transcriptome profiles of latently- and reactivated HIV-1 infected cells of 5 in vitro primary CD4 + T cell models of HIV-1 latency and 2 ex vivo studies of reactivated HIV-1 infected primary CD4 + T cells from HIV-1 infected individuals. Identifying genes that are differentially expressed between latently- and reactivated HIV-1 infected primary CD4 + T cells could be a more successful strategy to better understand and characterize HIV-1 latency and reactivation. We observed that natural ligands and coreceptors were predominantly downregulated in latently HIV-1 infected primary CD4 + T cells, whereas genes associated with apoptosis, cell cycle and HLA class II were upregulated in reactivated HIV-1 infected primary CD4 + T cells. In addition, we observed 5 differentially expressed genes that co-occurred in latently- and reactivated HIV-1 infected primary CD4 + T cells, one of which, MSRB2, was found to be differentially expressed between latently- and reactivated HIV-1 infected cells. Investigation of primary CD4 + T cell models of HIV-1 latency that mimic the in vivo state remains essential for the study of HIV-1 latency and thus providing the opportunity to compare the transcriptome profile of latently- and reactivated HIV-1 infected cells to gain insights into differentially expressed genes, which might contribute to HIV-1 latency.

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.

Although a correlation between polymorphisms of NOD-like receptor family-pyrin domain containing 3 (NLRP3) and predisposition to type 1 diabetes (T1D) has been identified, the potential function and activation of the NLRP3 inflammasome in T1D have not been clarified. The present study shows that non-obese diabetic mice exhibited increased NLRP3, and pro-IL-1β gene expression in pancreatic lymph nodes (PLNs). Similar increases in gene expression of NLRP3, apoptosis associated speck like protein (ASC) and pro-IL-1β were induced by multiple low doses of streptozotocin (STZ) in C57BL/6 mice. In addition, diabetic C57BL/6 mice also exhibited increased IL-1β protein expression in the pancreatic tissue at day 7, which remained elevated until day 15. Diabetic mice also showed increased positive caspase-1 macrophages in the PLNs, which were decreased in NLRP3 mice, but not in ASC mice, after STZ treatment. NLRP3- and IL-1R-deficient mice, but not ASC-deficient mice, showed reduced incidence of diabetes, less insulitis, lower hyperglycemia, and normal insulin levels compared to wild-type (WT) diabetic mice. Notably, these mice also displayed a decrease in IL-17-producing CD4 and CD8 T cells (Th17 and Tc17) and IFN-γ-producing CD4 and CD8 T cells (Th1 and Tc1) in the PLNs. Following STZ treatment to induce T1D, NLRP3-deficient mice also exhibited an increase in myeloid-derived suppressor cell and mast cell numbers in the PLNs along with a significant increase in IL-6, IL-10, and IL-4 expression in the pancreatic tissue. Interestingly, diabetic mice revealed increased circulating expression of genes related to mitochondrial DNA, such as cytochrome and cytochrome , but not NADH dehydrogenase subunit 6 (NADH). Mitochondrial DNA (mDNA) from diabetic mice, but not from non-diabetic mice, induced significant IL-1β production and caspase-1 activation by WT macrophages, which was reduced in NLRP3 macrophages. Finally, mDNA administration increased Th17/Tc17/Th1/Tc1 cells in the PLNs and precipitated T1D onset, which was abolished in NLRP3 mice. Overall, our results demonstrate that mDNA-mediated NLRP3 activation triggers caspase-1-dependent IL-1β production and contributes to pathogenic cellular responses during the development of STZ-induced T1D.

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.

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.