Role In CD8 Research Articles

Transcription factor Nfil3 is a regulator of CD8 T cell differentiation in mouse Influenza A infection

Abstract After an acute respiratory infection is cleared, most T cells that controlled the infection die off. Tissue resident memory CD8 T cells (T RM) remain in the lung, poised to fight off a recurrent infection. These T RMhave large impacts on the survival and morbidity of subsequent infection. While many have studied this subset to understand what causes differentiation into this essential T cell subset, a master regulator of this phenotype remains elusive. To these ends, RNA and ATAC sequencing experiments of T RMwere conducted after viral clearance to investigate the existence of a master regulator. Transcription factor Nfil3 became a likely candidate after integrated omics analyses. Flow cytometry to fully characterize the levels of Nfil3 in all T cell subsets of the lung, spleen, and draining lymph node was conducted 7, 14, and 43 days post infection (dpi). At days 7 and 14 dpi, Nfil3 correlated with pre-T RMmarkers. At 43 dpi, Nfil3 was highest in T RMand lowest in central memory T cells. Finally, experiments were performed to investigate if Nfil3 played a causal role in T RMdevelopment or maintenance. T cells were transduced with Nfil3 overexpression constructs and adoptively transferred into mice, which were then infected. Notable changes in differentiation were observed between treatment and control. T cell proliferation was also affected ex vivoin a proliferation dye assay, implying that Nfil3 plays a role in the acute response. Finally, using a CD8-specific inducible floxout system, Nfil3 was floxed out during acute infection, recently post viral-clearance, and 6 weeks after during the memory phase to appreciate the effect on T cell differentiation. Overall, we argue Nfil3 plays a role in CD8 T cell differentiation in respiratory infections. This work was funded by a Program Project grant through the National Institutes of Health, National Institute of Allergy and Infectious Diseases P01-AI102851 and through the National Institutes of Health training grant T32GM007356-46 and the National Institutes of Health training grant T32HL066988-20.

Role of CD19+ CD5+ CD1d+ Bregs in maintaining the Th17/Treg balance in mice with systemic lupus erythematosus complicated with atherosclerosis.

In this study, we aimed to investigate Bregs, their regulatory effects on Th17/Treg cell balance, and the release of downstream inflammatory factors in a mouse model of low-density lipoprotein receptor (LDLr)-/- + Pristane. After the establishment of the mouse model of systemic lupus erythematosus (SLE) complicated with atherosclerosis (AS), 8-week-old LDLr-/- + Pristane mice (n = 10) were included in the SLE + AS group. Furthermore, 8-week-old MRL/lpr and C57 mice were used as the SLE and normal control groups, respectively (n = 10 per group). After feeding the mice a high-fat diet for 14 weeks, peripheral blood and spleen of mice were collected, and Bregs, Th17, and Treg cells and related inflammatory factors were detected by flow cytometry, enzyme-linked immunosorbent assay, and reverse-transcription polymerase chain reaction. The number of Bregs and Tregs in spleen lymphocytes of SLE + AS mice significantly decreased compared with the C57 group (p < .05), whereas the number of Th17 cells significantly increased (p = .000). Furthermore, the proportion of Bregs showed a negative correlation with the Th17/Treg ratio (p = .03). Mice in the SLE + AS group showed higher serum interleukin (IL)-10, IL-17, and tumor necrosis factor-α levels than those in the SLE and C57 groups (p < .05). Furthermore, IL-35 and transforming growth factor (TGF)-β expression was reduced in the SLE + AS group compared with the C57 group (p < .05). The proportion of Breg decreases was negatively associated with increased Th17/Treg which was increased in SLE + AS mice, indicating that Bregs may regulate Th17/Treg cell homeostasis and cytokine release via IL-35 and TGF-β production.

Metabolic Challenges in Anticancer CD8 T Cell Functions.

Cancer immunotherapies continue to face numerous obstacles in the successful treatment of solid malignancies. While immunotherapy has emerged as an extremely effective treatment option for hematologic malignancies, it is largely ineffective against solid tumors due in part to metabolic challenges present in the tumor microenvironment (TME). Tumor-infiltrating CD8+ T cells face fierce competition with cancer cells for limited nutrients. The strong metabolic suppression in the TME often leads to impaired T-cell recruitment to the tumor site and hyporesponsive effector functions via T-cell exhaustion. Growing evidence suggests that mitochondria play a key role in CD8+ T-cell activation, migration, effector functions, and persistence in tumors. Therefore, targeting the mitochondrial metabolism of adoptively transferred T cells has the potential to greatly improve the effectiveness of cancer immunotherapies in treating solid malignancies.

The aryl hydrocarbon receptor cell intrinsically promotes resident memory CD8+ T cell differentiation and function

The Aryl hydrocarbon receptor (Ahr) regulates the differentiation and function of CD4+ Tcells; however, its cell-intrinsic role in CD8+ Tcells remains elusive. Herein we show that Ahr acts as a promoter of resident memory CD8+ Tcell (TRM) differentiation and function. Genetic ablation of Ahr in mouse CD8+ Tcells leads to increased CD127-KLRG1+ short-lived effector cells and CD44+CD62L+ T central memory cells but reduced granzyme-B-producing CD69+CD103+ TRM cells. Genome-wide analyses reveal that Ahr suppresses the circulating while promoting the resident memory core gene program. A tumor resident polyfunctional CD8+ Tcell population, revealed by single-cell RNA-seq, is diminished upon Ahr deletion, compromising anti-tumor immunity. Human intestinal intraepithelial CD8+ Tcells also highly express AHR that regulates invitro TRM differentiation and granzyme B production. Collectively, these data suggest that Ahr is an important cell-intrinsic factor for CD8+ Tcell immunity.

Differential expression of CD8 defines phenotypically distinct cytotoxic T cells in cancer and multiple sclerosis.

Cytotoxic T lymphocytes take on a leading role in many immune-related diseases. They function as key effector immune cells fighting cancer cells, but they are also considerably involved in autoimmune diseases. Common to both situations, CD8+ T cells need to adapt their metabolism and effector function to the harsh and nutrient-deprived conditions of the disease-associated microenvironment. We used an in vitro starvation as well as rapamycin treatment protocol mimicking nutrient deprivation to generate CD8Low versus CD8High T cells and performed FACS-Sorting followed by transcriptomic profiling of the cytotoxic T cell subsets. Prominent markers identified in the CD8Low versus the CD8High T cells were then used to investigate the presence of these cell subsets in immune-related human diseases. Employing cancer tissue microarrays and PhenOptics multispectral imaging as well as flow cytometry, we studied these CD8+ T cell subsets in cancer and relapsing-remitting multiple sclerosis patients. Starvation induced a decreased expression of CD8, yielding a CD8Low T cell subpopulation with an altered transcriptomic signature and reduced effector function. CD8Low T cell showed enhanced ST2L and IL6ST (CD130) expression compared to CD8High T cells which expressed elevated KLRD1 (CD94) and granzyme B levels within the tumour microenvironment (TME). Spatial analysis revealed the presence of CD8High T cells in close proximity to tumour cells, while the CD8Low T cells resided at the tumour boundaries. Importantly, the number of tumour-infiltrating CD8Low T lymphocytes correlated with a poor prognosis as well as with enhanced cancer progression in human mammary carcinoma. We also found a reduced frequency of CD8Low T lymphocytes in a cohort of relapse (disease active) multiple sclerosis patients compared to healthy subjects during immune cell starvation in vitro. In summary, our data show that functionally distinct cytotoxic T lymphocytes can be identified based on their expression of CD8. Indicating a more general role in CD8 T cell immunity, these cells may play opposing roles in the TME, and also in the pathophysiology of autoimmune diseases such as multiple sclerosis.

Role of CNSs Conserved Distal Cis-Regulatory Elements in CD4 + T Cell Development and Differentiation.

Naïve CD4+ T cells differentiate into diverse subsets of effector cells and perform various homeostatic and immune functions. The differentiation and maintenance of these different subsets are controlled through the upregulation and silencing of master genes. Mechanistic studies of the regulation of these master genes identified conserved and distal intronic regulatory elements, which are accessible subsets of conserved non-coding sequences (CNSs), acting as cis-regulatory elements in a lineage-specific manner that controls the function of CD4+ T cells. Abnormal CNS activity is associated with incorrect expression of master genes and development of autoimmune diseases or immune suppression. Here, we describe the function of several conserved, distal cis-regulatory elements at the Foxp3, Rorc, Il-4, Il-10 and Il-17 gene locus were shown to play important roles in CD4+ T cells differentiation. Together, this review briefly outlines currently known CNSs, with a focus on their regulations and functions in complexes modulating the differentiation and maintenance of various CD4+ T cells subsets, in health and disease contexts, as well as during the conversion of T regulatory cells to T helper 17 cells. This article will provide a comprehensive view of CNSs conserved distal cis-regulatory elements at a few loci that control aspects of CD4+ T cells function.

Interactions with Asialo-Glycoprotein Receptors and Platelets Are Dispensable for CD8+ T Cell Localization in the Murine Liver.

Liver-resident CD8+ T cells can play critical roles in the control of pathogens, including Plasmodium and hepatitis B virus. Paradoxically, it has also been proposed that the liver may act as the main place for the elimination of CD8+ T cells at the resolution of immune responses. We hypothesized that different adhesion processes may drive residence versus elimination of T cells in the liver. Specifically, we investigated whether the expression of asialo-glycoproteins (ASGPs) drives the localization and elimination of effector CD8+ T cells in the liver, while interactions with platelets facilitate liver residence and protective function. Using murine CD8+ T cells activated in vitro, or in vivo by immunization with Plasmodium berghei sporozoites, we found that, unexpectedly, inhibition of ASGP receptors did not inhibit the accumulation of effector cells in the liver, but instead prevented these cells from accumulating in the spleen. In addition, enforced expression of ASGP on effector CD8+ T cells using St3GalI-deficient cells lead to their loss from the spleen. We also found, using different mouse models of thrombocytopenia, that severe reduction in platelet concentration in circulation did not strongly influence the residence and protective function of CD8+ T cells in the liver. These data suggest that platelets play a marginal role in CD8+ T cell function in the liver. Furthermore, ASGP-expressing effector CD8+ T cells accumulate in the spleen, not the liver, prior to their destruction.

Mechanism of Tim-3 regulation of CD8+ T cell function

Abstract Tim-3 or transmembrane immunoglobulin and mucin domain-3 is a type I membrane protein expressed by various immune cell types, and has been shown to have a co-stimulatory role in T cells through the PI3K pathway. Tim-3 comprises extracellular, transmembrane and intracellular domains, the latter of which contains five tyrosine residues. We and others have shown that these tyrosines participate in TCR-mediated signaling pathways. Using LCMV infection, we also found that Tim-3 expression influences the formation of short-lived effector and memory precursor CD8+ T cells. We hypothesize that Tim-3 signaling through the tyrosine residues in its cytoplasmic domain modulates CD8+ T cell activation and differentiation. To test this hypothesis, we have used LCMV-specific TCR transgenic (P14) mice crossed to truncated version of Tim-3 and CD8+ conditional deletion of Tim-3. CD8+ T cell activation and memory were analyzed by flow cytometry after infection with LCMV Armstrong to induce an acute infection. The effects of Tim-3 on CD8+ T cells were found to be most prominent at the effector stage of infection and RNA sequencing has shown that loss of Tim-3 signaling promotes acquisition of a memory-like phenotype. Transcription factors T-bet and Blimp-1 were found to be lower in Tim-3 KO CD8+ T cells, while Tcf-1 maintained at higher levels in the absence of Tim-3 signaling. Cytokine production by effector CD8+ T cells was also found to be lower when Tim-3 was absent. Thus, we conclude that Tim-3 signaling via its cytoplasmic tyrosine residues plays a role in CD8+ T cells in an acute infection. These results may lead to a better understanding of CD8+ T cell activation and memory development in different settings. Supported by R01 AI138504-01A1

Exploring the role of c-Myc in defining the fate of exhausted CD8 T cells

Abstract c-Myc is a major transcription factor expressed upon activation of CD8 T cells that drives their clonal expansion and metabolism. The role of c-Myc in regulating the outcome of exhausted CD8 T cells during chronic infection and cancer remains poorly defined. In this study, we used a unique model of c-Myc conditional ablation following antigen priming of CD8 T cells to investigate whether c-Myc exerts a role in CD8 T cell exhaustion in chronic antigenic settings. Our studies show that targeted deficiency of c-Myc in antigen-specific CD8 T cells resulted in decreased cell numbers but promoted the generation of stem-cell-like TCF-1+ less exhausted CD8 T cells. These cells are key therapeutic target for overcoming CD8+ T cells exhaustion by providing the proliferative burst after PD1 checkpoint blockade immunotherapy (CBI). We, therefore combined anti-PD-L1 therapy and c-Myc inhibition to determine whether c-Myc inhibition might synergize to improve the therapeutic outcome. Our data using c-Myc inhibitor alone revealed an increased frequency of TCF-1+ CD8 T cells. However, the number of antigen specific CD8 T cells and the production of effector cytokines (IFN-γ and TNF-α) remained identical to untreated group. Notably, the combination of c-Myc inhibitor and PD-1 CBI significantly promoted the proliferation of antigen-specific CD8 T cells and the production of IFN-γ and TNF-α. Overall, findings support a role for c-Myc in defining the fate of exhausted CD8 T cells, and illustrate a potential pathway for the optimization of check point blockade immunotherapy of chronic infections and cancer. Supported by NIH R21AI154363 NIH R01AI32819

The TOX subfamily: all-round players in the immune system.

The thymocyte selection-related HMG box protein (TOX) subfamily comprises evolutionarily conserved DNA-binding proteins, and is expressed in certain immune cell subsets and plays key roles in the development of CD4+ T cells, innate lymphoid cells (ILCs), T follicular helper (Tfh) cells, and in CD8+ T-cell exhaustion. Although its roles in CD4+ T and natural killer (NK) cells have been extensively studied, recent findings have demonstrated previously unknown roles for TOX in the development of ILCs, Tfh cells, as well as CD8+ T-cell exhaustion; however, the molecular mechanism underlying TOX regulation of these immune cells remains to be elucidated. In this review, we discuss recent studies on the influence of TOX on the development of various immune cells and CD8+ T-cell exhaustion and the roles of specific TOX family members in the immune system. Moreover, this review suggests candidate regulatory targets for cell therapy and immunotherapies.

Distinct Role of TNFR1 and TNFR2 in Protective Immunity Against Orientia tsutsugamushi Infection in Mice.

Infection with Orientia tsutsugamushi, an obligate intracellular bacterium, can cause mild or severe scrub typhus. Some patients develop acute lung injury, multi-organ failure, and fatal infection; however, little is known regarding key immune mediators that mediate infection control or disease pathogenesis. Using murine models of scrub typhus, we demonstrated in this study the requirement of TNF-TNFR signaling in protective immunity against this infection. Mice lacking both TNF receptors (TNFR1 and TNFR2) were highly susceptible to O. tsutsugamushi infection, displaying significantly increased tissue bacterial burdens and succumbing to infection by day 9, while most wild-type mice survived through day 20. This increased susceptibility correlated with poor activation of cellular immunity in inflamed tissues. Flow cytometry of lung- and spleen-derived cells revealed profound deficiencies in total numbers and activation status of NK cells, neutrophils, and macrophages, as well as CD4 and CD8 T cells. To define the role of individual receptors in O. tsutsugamushi infection, we used mice lacking either TNFR1 or TNFR2. While deficiency in either receptor alone was sufficient to increase host susceptibility to the infection, TNFR1 and TNFR2 played a distinct role in cellular responses. TNF signaling through TNFR1 promoted inflammatory responses and effector T cell expansion, while TNFR2 signaling was associated with anti-inflammatory action and tissue homeostasis. Moreover, TNFRs played an intrinsic role in CD8+ T cell activation, revealing an indispensable role of TNF in protective immunity against O. tsutsugamushi infection.

Sialomucin CD43 Plays a Deleterious Role in the Development of Experimental Heart Failure Induced by Pressure Overload by Modulating Cardiac Inflammation and Fibrosis.

Sialomucin CD43 is a transmembrane protein differentially expressed in leukocytes that include innate and adaptive immune cells. Among a variety of cellular processes, CD43 participates in T cell adhesion to vascular endothelial cells and contributes to the progression of experimental autoimmunity. Sequential infiltration of myeloid cells and T cells in the heart is a hallmark of cardiac inflammation and heart failure (HF). Here, we report that CD43−/− mice have improved survival to HF induced by transverse aortic constriction (TAC). This enhanced survival is associated with improved systolic function, decreased cardiac fibrosis, and significantly reduced T cell cardiac infiltration in response to TAC compared to control wild-type (WT) mice. Lack of CD43 did not alter the number of myeloid cells in the heart, but resulted in decreased cardiac CXCL10 expression, a chemoattractant for T cells, and in a monocyte shift to anti-inflammatory macrophages in vitro. Collectively, these findings unveil a novel role for CD43 in adverse cardiac remodeling in pressure overload induced HF through modulation of cardiac T cell inflammation.

CD4 T Cell-Mediated Immune Control of Cytomegalovirus Infection in Murine Salivary Glands.

CD4 T cells are well known for their supportive role in CD8 T cell and B cell responses during viral infection. However, during murine cytomegalovirus (MCMV) infection in the salivary glands (SGs), CD4 T cells exhibit direct antiviral effector functions to control the infection. In this mucosal organ, opposed to other infected tissues, MCMV establishes a sustained lytic replication that lasts for several weeks. While the protective function of CD4 T cells is exerted through the production of the pro-inflammatory cytokines interferon gamma (IFNγ) and tumor necrosis factor alpha (TNF), the reasons for their markedly delayed control of lytic MCMV infection remain elusive. Here, we review the current knowledge on the dynamics and mechanisms of the CD4 T cell-mediated control of MCMV-infected SGs, including their localization in the SG in relation to MCMV infected cells and other immune cells, their mode of action, and their regulation.

Repression of CRNDE enhances the anti-tumour activity of CD8+T cells against oral squamous cell carcinoma through regulating miR-545-5p and TIM-3.

Immunotherapy has been identified a promising treatment of cancers, including Oral squamous cell carcinoma (OSCC). CRNDE is highly overexpressed in various cancers. Many lncRNAs have been reported in CD8 T lymphocytes. Little is investigated about their effects in the functions of CD8 + T cells in OSCC. Currently, the influence of lncRNA CRNDE on the function of CD8 + T cells in OSCC progression was investigated. Here, CRNDE was obviously elevated and negatively correlated with IFN‐γ production in tumour‐infiltrating CD8 + T cells isolated from OSCC patients. CRNDE can exhibit a crucial role in activating CD8 + T‐cell exhaustion. Mechanistically, CRNDE specifically sponged miR‐545‐5p to induce T‐cell immunoglobulin and mucin domain‐3 (TIM‐3), thus contributing to CD8 + T‐cell exhaustion. The function of miR‐545‐5p on T‐cell function remains poorly known. TIM‐3 is a significant immune checkpoint, and it inhibits cancer immunity. TIM‐3 can demonstrate an important role in CD8 + T‐cell exhaustion. In summary, loss of CRNDE could induce miR‐545‐5p and inhibit TIM3 expression, thus significantly activated the anti‐tumour effect of CD8 + T cells.

Screening and Prognostic Analysis of Immune-Related Genes in Pancreatic Cancer.

Pancreatic cancer remains to have a high mortality, which is partly due to the lack of effective treatment strategies. In this study, genes with potential associations with immunophenotyping of pancreatic cancer were screened through bioinformatics analysis and the correlation between immune-related genes and the prognosis of pancreatic cancer patients was assessed. Firstly, differentially expressed immune genes were extracted from the pancreatic cancer-related datasets obtained for purposes of this study. The samples were processed by the “Consensus Cluster Plus” R package to determine the number of immune subtypes. Then, the pancreatic cancer immunophenotyping-related gene modules were determined. Differential analysis of immune gene modules was performed, and the function of genes related to pancreatic cancer immune subtypes was identified. The number of immune cells in the samples was calculated, followed by the differential expression analysis of immune cell numbers in each immune subtype of pancreatic cancer. The immune infiltration score was also estimated, and the correlation between the immune infiltration score and the patient prognosis with different immune subtypes was determined. Gene differences between each immune subtype were identified by differential expression analysis, and key immune genes affecting immunophenotyping were obtained. Following the analysis, 426 immune-related genes were identified to have potential involvement in the occurrence and development of pancreatic cancer, of which CD19 may be the most critical gene affecting the immunophenotyping of pancreatic cancer. CD19 played a significant role in the occurrence and development of IS2 and IS3 immune subtypes of pancreatic cancer through its action on B cells and T cells. Moreover, the expression of CD19 was increased in the collected pancreatic cancer tissues. Overall, our findings uncovered the critical role of CD19 in the prognosis of pancreatic cancer patients.

MicroRNA-7 overexpression positively regulates the CD8+ SP cell development via targeting PIK3R1

microRNA-7 (miR-7), a distinct miRNA family member, has been reported to be involved in the biological functions of immune cells. However, the potential role of miR-7 in the CD8+ T cell development remains to be elucidated. In this study, we estimated the potential effects of miR-7 overexpression in the thymic CD8+ SP cell development using miR-7 overexpression mice. Our results showed that compared with those in control wild type (WT) mice, the volume, weight and total cell numbers of thymus in miR-7 overexpression (OE) mice increased significantly. The absolute cell number of CD8+ SP cells in miR-7 OE mice increased and its ability of activation and proliferation enhanced. Futhermore, we clarified that miR-7 overexpression had an intrinsic promote role in CD8+ SP cell development by adoptive cell transfer assay. Mechanistically, the expression level of PIK3R1, a target of miR-7, decreased significantly in CD8+ SP cells of miR-7 OE mice. Moreover, the expression level of phosphorylated (p)-AKT and p-ERK changed inversely and indicating that miR-7 overexpression impaired the balance of AKE and ERK pathways. In summary, our work reveals an essential role of miR-7 in promoting CD8+ SP cell development through the regulation of PIK3R1 and balance of AKT and ERK pathways.

Pre-clinical development and molecular characterization of an engineered type 1 regulatory T-cell product suitable for immunotherapy

Background aimsAllogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapeutic approach for many hematological disorders. However, allo-HSCT is frequently accompanied by a serious side effect: graft-versus-host disease (GVHD). The clinical use of allo-HSCT is limited by the inability of current immunosuppressive regimens to adequately control GvHD without impairing the graft-versus-leukemia effect (GvL) conferred by transplanted healthy immune cells. To address this, the authors have developed an engineered type 1 regulatory T-cell product called CD4IL-10 cells. CD4IL-10 cells are obtained through lentiviral transduction, which delivers the human IL10 gene into purified polyclonal CD4+ T cells. CD4IL-10 cells may provide an advantage over standard-of-care immunosuppressants because of the ability to suppress GvHD through continuous secretion of IL-10 and enhance the GvL effect in myeloid malignancies through targeted killing of malignant myeloid cells. MethodsHere the authors established a production process aimed at current Good Manufacturing Practice (cGMP) production for CD4IL-10 cells. ResultsThe authors demonstrated that the CD4IL-10 cell product maintains the suppressive and cytotoxic functions of previously described CD4IL-10 cells. In addition, RNA sequencing analysis of CD4IL-10 identified novel transcriptome changes, indicating that CD4IL-10 cells primarily upregulate cytotoxicity-related genes. These include four molecules with described roles in CD8+ T and natural killer cell-mediated cytotoxicity: CD244, KLRD1, KLRC1 and FASLG. Finally, it was shown that CD4IL-10 cells upregulate IL-22, which mediates wound healing and tissue repair, particularly in the gut. ConclusionsCollectively, these results pave the way toward clinical translation of the cGMP-optimized CD4IL-10 cell product and uncover new molecules that have a role in the clinical application of CD4IL-10 cells.

Distinct roles of ICOS and CD40L in human T-B cell adhesion and antibody production

CD40-CD40L and inducible co-stimulatory molecule (ICOS)-ICOSL ligations are demonstrated to play critical roles in CD4+T-B interaction for B cell activation and differentiation in mouse models. Herein, by using a micropipette adhesion assay and an in vitro CD4+T-B cell coculture system simultaneously, we intended to dissect their roles in human CD4+T-B adhesion and IgG/IgM production. With the upregulation of CD40L and ICOS expressions on CD4+ T cells upon TCR/CD28 stimulation in vitro, activated CD4+ T cells exhibited enhanced adhesion with autologous B cells at a single cell level when compared to the resting counterparts. Blockade of ICOS dramatically damped the adhesion between CD4+ T and B cells whereas less effect of CD40L blockade was observed. On the contrary, blockade of CD40L led to the dramatic decrease in IgG/IgM production when B cells were cocultured with activated CD4+ T cells together with the decrease in the induction of CD19hi B cells. However, ICOS blockade displayed less attenuation on IgG/IgM production. Distinct roles of CD40-CD40L and ICOS-ICOSL in cell adhesion and IgG/IgM production were also observed in CD4+T-B cell interaction in system lupus erythematosus patients. The blockade of CD40L, rather than ICOS, led to the dramatic decrease in the phosphorylation of Pyk2 in CD19hi B cells and total B cells. Our study thus provides the evidence that CD40L and ICOS on activated CD4+ T cells either upon in vitro activation or at the pathogenic state function diversely during CD4+T-B cell interactions. While ICOS-ICOSL ligation is more likely to be engaged in cell adhesion, CD40-CD40L provides indispensable signal for B cell differentiation and IgG/IgM production. Our results are thus indicative for the segregating costimulation of CD40-CD40L and ICOS-ICOSL on CD4+ T cells for B cell activation and differentiation, which might be helpful for the dissection of SLE pathogenesis.

MiR-let-7i inhibits CD4+ T cell apoptosis in patients with acute coronary syndrome.

Abnormal CD4+ T cells appear in the peripheral blood of patients with acute coronary syndrome (ACS). Studies have confirmed that CD4+ T cells are resistant to apoptosis, but the specific mechanism has not been elucidated yet. The microRNA (miR)-let-7i plays an important regulatory role in the cardiovascular system and is widely involved in cell proliferation and apoptosis. In this study, we aimed to investigate its functional and regulatory roles in CD4+ T cell apoptosis. Apoptosis of CD4+ T cells was detected using TUNEL assay. Western blot analyses were used to detect the expression of Bcl-2 and Bax. Real-time polymerase chain reaction and western blot analyses were used to detect the expression of miR-let-7i, Fas and FasL. A miR-let-7i mimic or inhibitor was transfected into CD4+ T cells, and miR-let-7i activity was investigated using Cell Counting Kit-8 (CCK-8) and TUNEL assays. Apoptosis of CD4+ T cells in ACS patients was significantly decreased. Overexpression of miR-let-7i inhibited CD4+ T cell apoptosis and improved cell survival rates, while inhibition of miR-let-7i facilitated cell apoptosis. We also found that miR-let-7i negatively regulated Fas and FasL gene expression in CD4+ T cells. The present study identified that miR-let-7i significantly reduces Fas and FasL expression in ACS CD4+ T cells and inhibits apoptosis in these cells. Therefore, miR-let-7i may serve as a possible therapeutic target for the treatment of ACS.

CD47 in the Brain and Neurodegeneration: An Update on the Role in Neuroinflammatory Pathways.

CD47 is a receptor belonging to the immunoglobulin (Ig) superfamily and broadly expressed on cell membranes. Through interactions with ligands such as SIRPα, TSP-1, integrins, and SH2-domain bearing protein tyrosine phosphatase substrate-1 (SHPS-1), CD47 regulates numerous functions like cell adhesion, proliferation, apoptosis, migration, homeostasis, and the immune system. In this aspect, previous research has shown that CD47 modulates phagocytosis via macrophages, the transmigration of neutrophils, and the activation of T-cells, dendritic cells, and B-cells. Moreover, several studies have reported the increased expression of the CD47 receptor in a variety of diseases, including acute lymphoblastic leukemia (ALL), chronic myeloid leukemia, non-Hodgkin’s lymphoma (NHL), multiple myeloma (MM), bladder cancer, acute myeloid leukemia (AML), Gaucher disease, Multiple Sclerosis and stroke among others. The ubiquitous expression of the CD47 cell receptor on most resident cells of the CNS has previously been established through different methodologies. However, there is little information concerning its precise functions in the development of different neurodegenerative pathologies in the CNS. Consequently, further research pertaining to the specific functions and roles of CD47 and SIRP is required prior to its exploitation as a druggable approach for the targeting of various neurodegenerative diseases that affect the human population. The present review attempts to summarize the role of both CD47 and SIRP and their therapeutic potential in neurodegenerative disorders.