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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.

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.

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.

The transcription factor T cell factor-1 (TCF-1) is encoded by Tcf7 and plays a significant role in regulating immune responses to cancer and pathogens. TCF-1 plays a central role in CD4 T cell development; however, the biological function of TCF-1 on mature peripheral CD4 T cell-mediated alloimmunity is currently unknown. This report reveals that TCF-1 is critical for mature CD4 T cell stemness and their persistence functions. Our data show that mature CD4 T cells from TCF-1 cKO mice did not cause graft versus host disease (GvHD) during allogeneic CD4 T cell transplantation, and donor CD4 T cells did not cause GvHD damage to target organs. For the first time, we showed that TCF-1 regulates CD4 T cell stemness by regulating CD28 expression, which is required for CD4 stemness. Our data showed that TCF-1 regulates CD4 effector and central memory formation. For the first time, we provide evidence that TCF-1 differentially regulates key chemokine and cytokine receptors critical for CD4 T cell migration and inflammation during alloimmunity. Our transcriptomic data uncovered that TCF-1 regulates critical pathways during normal state and alloimmunity. Knowledge acquired from these discoveries will enable us to develop a target-specific approach for treating CD4 T cell-mediated diseases.

Background Polymyositis (PM) and dermatomyositis (DM) are two distinct subgroups of idiopathic inflammatory myopathies, a chronic inflammatory disorder clinically characterized by muscle weakness and inflammatory cell infiltrates in muscle tissue. In PM, a major component of inflammatory cell infiltrates is CD8+ T cells, whereas in DM, CD4+ T cells, plasmacytoid dendritic cells, and B cells predominate. In this study, with the aim to differentiate involvement of CD4+ and CD8+ T-cell subpopulations in myositis subgroups, we investigated transcriptomic profiles of T cells from peripheral blood of patients with myositis. Methods Total RNA was extracted from CD4+ T cells (PM = 8 and DM = 7) and CD8+ T cells (PM = 4 and DM = 5) that were isolated from peripheral blood mononuclear cells via positive selection using microbeads. Sequencing libraries were generated using the Illumina TruSeq Stranded Total RNA Kit and sequenced on an Illumina HiSeq 2500 platform, yielding about 50 million paired-end reads per sample. Differential gene expression analyses were conducted using DESeq2. Results In CD4+ T cells, only two genes, ANKRD55 and S100B , were expressed significantly higher in patients with PM than in patients with DM (false discovery rate [FDR] < 0.05, model adjusted for age, sex, HLA-DRB1 *03 status, and RNA integrity number [RIN]). On the contrary, in CD8+ T cells, 176 genes were differentially expressed in patients with PM compared with patients with DM. Of these, 44 genes were expressed significantly higher in CD8+ T cells from patients with PM, and 132 genes were expressed significantly higher in CD8+ T cells from patients with DM (FDR < 0.05, model adjusted for age, sex, and RIN). Gene Ontology analysis showed that genes differentially expressed in CD8+ T cells are involved in lymphocyte migration and regulation of T-cell differentiation. Conclusions Our data strongly suggest that CD8+ T cells represent a major divergence between PM and DM patients compared with CD4+ T cells. These alterations in the gene expression in T cells from PM and DM patients might advocate for distinct immune mechanisms in these subphenotypes of myositis.

Tissue‐resident memory CD4+ T cells (CD4+ TRMs) are pivotal in immune responses during inflammation and infection, yet their phenotype and function within the tumor microenvironment (TME) remain elusive. Here, we delineated CD4+ TRMs in non‐small cell lung cancer (NSCLC) using CD103 and CD69 as defining markers and demonstrated that their transcriptional and phenotypic profiles closely resembled those observed in murine models. Tumor‐infiltrating CD4+ TRMs exert helper antitumor effects by secreting the chemokine XCL1 to recruit conventional type 1 dendritic cells (cDC1s), facilitating antigen presentation and priming cytotoxic T lymphocyte responses. Mechanistically, we identified the costimulatory molecule JAML as essential for CD4+ TRM‐mediated cDC1 mobilization. Compared with their counterparts in normal lung tissue, tumor‐infiltrating CD4+ TRMs exhibited elevated expression of immune checkpoint molecules, indicating a dysfunctional state, accompanied by significantly reduced XCL1 expression. PD‐1 signaling within the NSCLC TME suppressed JAML expression—an effect reversible by PD‐1 blockade—while the administration of a JAML agonist further enhanced the antitumor efficacy of PD‐1 inhibitors in tumor‐bearing mice. Clinically, the presence of XCL1‐secreting CD4+ TRMs positively correlated with favorable clinical outcomes and enhanced responses to anti‐PD‐1 immunotherapy in NSCLC patients. Our findings reveal a critical role for JAML in facilitating CD4+ TRM‐mediated cDC1 mobilization within the NSCLC TME and highlight the translational potential of targeting CD4+ TRMs to enhance the efficacy of immune checkpoint blockade therapies.