Journal: Immunology letters
The transcription factor Krüppel-like factor 4 (KLF4) can activate or repress gene expression in a cell-context dependent manner. We have previously shown that KLF4 inhibits the proliferation of naïve CD8(+) T cells in vitro downstream of the transcription factor ELF4. In this work, we describe a novel role of KLF4 in the differentiation of CD8(+) T cells upon infection. Loss of KLF4 had minimal effect on thymic T cell development and distribution of mature T cells in the spleen, blood, and lymph nodes. KLF4-deficient naïve CD8(+) T cells also displayed normal homeostatic proliferation upon adoptive transfer into lymphopenic hosts. However, activation of KLF4-deficient naïve CD8(+) T cells by in vitro TCR crosslink and co-stimulation resulted in increased proliferation. Furthermore, naïve KLF4-deficient OT-I CD8(+) T cells generated increased numbers of functional memory CD8(+) T cells compared to wild type OT-I CD8(+) T cells co-injected in the same recipient in both primary and recall responses to Listeria monocytogenes-OVA. Collectively, our data demonstrate that KLF4 regulates differentiation of functional memory CD8(+) T cells while sparing development and homeostasis of naïve CD8(+) T cells.
To explore the genetic association of single nucleotide polymorphisms(SNP) in the coding region of the NOTCH4, exon 3 C+1297T and exon 5 A+3063G, in a case-control analysis of 58 Rheumatoid arthritis (RA) and 98 Alopecia areata (AA) and 100 ethnically matched healthy subjects. NOTCH4 polymorphisms were genotyped by standard PCR followed by restriction digestion. Analysis of C+1297T SNP revealed a significant association of allele C+1297 (p=0.03,OR=1.66,95%CI1.04-2.64) and Genotype CT (p=0.002,OR=2.82,95%CI 1.42-5.59) with susceptibility to RA. Analysis of A+3063G SNP revealed a significant association of allele A+3063 (p=0.05,OR=0.59,95%CI 0.35-1.008) genotype AA (p=0.002,OR=0.39,95%CI 0.17-0.87) with RA. Over all analysis between Alopecia patients and the studied SNPs failed to show any significant association. Classifying the patients by severity of disease, confined the risk role of CT genotype to the severest form of alopecia universalis (p=0.006,OR=3.82,95%CI 1.39-3.82) and AG genotype to semiuniversalis alopecia(p=0.004,OR=4.3,95%CI 1.5-15.3). Present study is the first to report a statistically significant association between RA and NOTCH4 polymorphisms.
The CC chemokine monocyte chemoattractant protein (MCP)-1/CCL2 is involved in the formation, progression, and destabilization of atheromatous plaques and plays an essential role in postinfarction remodeling. The aim of the present study was to evaluate the role of MCP-1 gene polymorphisms as susceptibility markers for premature coronary artery disease (CAD) and cardiovascular risk factors in the Mexican population. Four MCP-1 gene polymorphisms (rs1024611, rs2857654, rs3760396, and rs1024610) were genotyped by 5' exonuclease TaqMan assays in a group of 1072 patients with premature CAD, and 1082 healthy unrelated controls (with negative calcium score by computed tomography) seeking for associations with premature CAD and other metabolic and cardiovascular risk factors using logistic regression analyses. MCP-1 polymorphism frequencies were similar in premature CAD patients and healthy controls. When the analysis included only those premature CAD patients without type 2 diabetes mellitus (T2DM), the rs1024610 polymorphism was associated with increased risk of developing premature CAD under dominant and additive models adjusted by age and gender (OR = 1.33, Pdom = 0.040 and OR = 1.34, Padd = 0.027). The effect of the MCP-1 polymorphisms on various metabolic cardiovascular risk factors and metabolic parameters was explored separately in controls, and premature CAD. In this analysis adjusted by age and gender, the rs3760396 CC genotype was associated with low levels of gamma-glutamyl transpeptidase (P = 0.002), whereas, the rs1024610 TT genotype was associated with decreased risk of T2DM (P = 0.035) in premature CAD patients. One haplotype (CATG) was associated with increased risk of developing premature CAD (OR = 1.44, P = 0.0019). In summary, in our study, the rs1024610 polymorphism was associated with increased risk of developing premature CAD only in those patients without T2DM. The four MCP-1 polymorphisms were in high linkage disequilibrium and one haplotype was significantly associated with risk of developing premature CAD.
Norovirus (NoV) is now recognized as a major cause of gastroenteritis outbreaks, worldwide. Norovirus replication mechanisms are still poorly understood, mainly because a reliable cell culture system is still lacking. The present study aims at understanding some aspects of the immune response against norovirus, and particularly the capacity of virus like particles (VLPs) from an Italian strain, belonging to the GII.4 genotype predominating worldwide, to interact with target cells via Toll Like Receptors (TLRs). The capacity of GII.4 NoV VLPs to interact and cause the activation of TLR2, 4 and 5 was studied in recombinant HEK cells. The results obtained show the ability of GII.4 NoV VLPs to induce activation of TLR2 and 5. The results on TLRs activation confirm that GII.4 NoV VLPs interact with human intestinal cells and that TLR2 and 5 may represent putative receptors.
Innate lymphoid cells (ILC) including NK cells (cytotoxic) and the recently identified “helper” ILC1, ILC2 and ILC3, play an important role in innate defenses against pathogens. Notably, they mirror analogous T cell subsets, regarding the pattern of cytokine produced, while the timing of their intervention is few hours vs days required for T cell-mediated adaptive responses. On the other hand, the effectiveness of ILC in anti-tumor defenses is controversial. The relevance of NK cells in the control of tumor growth and metastasis has been well documented and they have been exploited in the therapy of high risk leukemia in the haploidentical hematopoietic stem cell transplantation setting. In contrast, the actual involvement of helper ILCs remains contradictory. Thus, while certain functional capabilities of ILC1 and ILC3 may favor anti-tumor responses, other functions could rather favor tumor growth, neo-angiogenesis, epithelial-mesenchymal transition and metastasis. In addition, ILC2, by secreting type-2 cytokines, are thought to induce a prevalent pro-tumorigenic effect. Finally, the function of both NK cells and helper ILCs may be inhibited by the tumor microenvironment, thus adding further complexity to the interplay between ILC and tumors.
Myokines are peptides produced and released by myocytes of muscle fibers that influence physiology of muscle and other organs and tissues. They are involved in mediating the beneficial effects that exercise has on health. More than one hundred have been identified and among them are IL6, myostatin, irisin, mionectin and decorin. Physical inactivity leads to an altered response of the secretion of myokines and resistance to them; this leads to a pro-inflammatory state that favors sarcopenia and fat accumulation, promoting the development of cardiovascular diseases, insulin resistance, and diabetes mellitus type 2. Some myokines, including irisin, are responsible for the improvement that exercise produces in many chronic diseases such as type 2 diabetes and cardiovascular diseases, some types of cancer and many autoimmune diseases such as idiopathic inflammatory myopathy, rheumatoid arthritis, systemic lupus erythematosus and inflammatory bowel disease.
Blockade of immune checkpoints has emerged as key strategy in the development of effective cancer therapies. In contrast to cell surface checkpoints like CTLA-4 and PD-1, however, additional cancer therapeutic targets are located inside the effector immune cells. Targeting these alternative checkpoints in cancer immunotherapy with the goal to strengthen the patient’s immune system are likely to extend the benefits of cancer immunotherapy in the near future. Along this line, we have defined and validated the orphan nuclear receptor NR2F6 (nuclear receptor subfamily 2 group F member 6, also called Ear-2) as an intracellular immune checkpoint in effector T cells. NR2F6 acts as a novel master switch of antitumor responses against both transplantable and spontaneous tumors in mice relevant for human cancer. NR2F6 directly represses transcription of key cytokine genes in T effector cells relevant for tumor cell rejection, such as IL-2, IFNƴ\ and TNFα. Thus, in the presence of NR2F6, T cell activation is limited within the tumor microenvironment. This defines NR2F6 as a key checkpoint governing the amplitude of cancer immune surveillance. Based on our study, an approach shall be initiated to identify low molecular weight compounds that selectively interfere with NR2F6 function in the clinic. Non-standard abbreviations used: AP-1, activation protein 1; CTLA-4, cytotoxic T lymphocyte-associated protein-4; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL-2, interleukin 2; IFNƴ, interferon ƴ; NFAT, nuclear factor of activated T cells; NR2F6, nuclear receptor subfamily 2, group F, member 6 - alias: Ear2/COUP-TFIII; PD-1/PD-L1, programmed cell death-1 and its ligand-1; PKC, protein kinase C; RORC, retinoid-related orphan receptor ƴ - alias: RORƴt or NR1F3; TCR, T cell receptor; TIL, tumor infiltrating lymphocyte; TNFα, tumor necrosis factor α.
We identified IL-17A-positive neutrophils in Wolbachia-positive Onchocerca volvulus nodules using an antibody that has previously reported IL-17A-positive neutrophils in several inflammatory conditions. However, we could not detect IL-17A using a range of alternative assays. Our data question the IL-17A antibody specificity and the ability of human neutrophils to express IL-17A.
Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by deficits in social interactions, communication, and increased stereotypical repetitive behaviors. The immune system plays an important role in neurodevelopment, regulating neuronal proliferation, synapse formation and plasticity, as well as removing apoptotic neurons. Immune dysfunction in ASD has been repeatedly described by many research groups across the globe. Symptoms of immune dysfunction in ASD include neuroinflammation, presence of autoantibodies, increased T cell responses, and enhanced innate NK cell and monocyte immune responses. Moreover these responses are frequently associated with more impairment in core ASD features including impaired social interactions, repetitive behaviors and communication. In mouse models replacing immune components in animals that exhibit autistic relevant features leads to improvement in behavior in these animals. Taken together this research suggests that the immune dysfunction often seen in ASD directly affects aspects of neurodevelopment and neurological processes leading to changes in behavior. Discussion of immune abnormalities in ASD will be the focus of this review.
Previous study showed that injection of thymopentin (TP 5) in the area of supramammary lymph nodes (SMLN) had therapeutic effect on the intramammary infection (IMI) in cows. This study was to explore the underlying mechanisms by investigating the immunomodulatory effect of TP 5 on SMLN lymphocytes. Lymphocyte proliferation, cell cycle distribution and cytokine mRNA expression were determined by MTT, FCM and RT-qPCR, respectively. Laser scanning confocal microscope (LSCM) was used to observe the binding between TP 5 and SMLN lymphocytes. Moreover, RNA-sequencing (RNA-seq) was performed to observe the difference between the lymphocytes with and without TP 5 treatment. The results showed that TP 5 significantly promoted lymphocyte proliferation, accelerated cell cycle progression, and enhanced mRNA expression of IL-17A and IL-17 F. Laser scanning confocal microscopic analysis revealed the binding of TP 5 to the surface of SMLN lymphocytes. A total of 1094 genes were identified as differentially expressed genes (DEGs) using RNA-seq with 692 up- and 402 down-regulated genes. 48 significantly enriched GO terms were identified by RNA-seq. In KEGG analysis, 1/3 of DEGs were enriched in the immune system pathway, including IL-17 signaling pathway, cytokine-cytokine receptor interaction, Th1 and Th2 cell differentiation, T cell receptor signaling pathway, Th17 cell differentiation. Among them, IL-17 signaling pathway was the most prominent. This study suggested that the therapeutic benefit of TP 5 in the treatment of bovine mastitis might be attributed to its immunomodulatory activity in SMLN lymphocytes.