Interferon regulatory factor 4 differentially regulates the production of Th2 cytokines in naive vs. effector/memory CD4+ T cells.
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ABSTRACT:
SUBMITTER: Honma K
PROVIDER: S-EPMC2572975 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Naïve CD4 T (NCD4T) cells post-activation undergo programming for inducible production of cytokines leading to generation of memory cells with various functions. Based on cytokine based polarization of NCD4T cells in vitro, programming for either 'Th1' (interferon-gamma [IFNg]) or 'Th2' (interleukin [IL]-4/5/13) cytokines is thought to occur via mutually exclusive expression and functioning of T-bet or GATA-3 transcription factors (TFs). However, we show that a high proportion of mouse and human memory-phenotype CD4 T (MCD4T) cells generated in vivo which expressed either Th1 or Th2 cytokines commonly co-expressed T-bet and GATA-3. While T-bet levels did not differ between IFNg-expressing and IL-4/5/13-expressing MCD4T cells, GATA-3 levels were higher in the latter. These observations were also confirmed in MCD4T cells from FVB/NJ or aged C57BL/6 or IFNg-deficient mice. While MCD4T cells from these strains showed greater Th2 commitment than those from young C57BL/6 mice, pattern of co-expression of TF was similar. Effector T cells generated in vivo following immunization also showed TF co-expression in Th1 or Th2 cytokine producing cells. We speculated that the difference in TF expression pattern of MCD4T cells generated in vivo and those generated in cytokine polarized cultures in vitro could be due to relative absence of polarizing conditions during activation in vivo. We tested this by NCD4T cell activation in non-polarizing conditions in vitro. Anti-CD3 and anti-CD28-mediated priming of polyclonal NCD4T cells in vitro without polarizing milieu generated cells that expressed either IFNg or IL-4/5/13 but not both, yet both IFNg- and IL-4/5/13-expressing cells showed upregulation of both TFs. We also tested monoclonal T cell populations activated in non-polarizing conditions. TCR-transgenic NCD4T cells primed in vitro by cognate peptide in non-polarizing conditions which expressed either IFNg or IL-4/5/13 also showed a high proportion of cells co-expressing TFs, and their cytokine commitment varied depending on genetic background or priming conditions, without altering pattern of TF co-expression. Thus, the model of mutually antagonistic differentiation programs driven by mutually exclusively expressed T-bet or GATA-3 does not completely explain natural CD4 T cell priming outcomes.
| S-EPMC5663332 | biostudies-literature
Project description:Cytokine receptors can be markers defining different T-cell subsets and considered as therapeutic targets. The association of IL-6 and IL-6 receptor ? (IL-6R?) with asthma was reported, suggesting their involvement in asthma.To determine whether and how IL-6R? defines a distinct effector memory (EM) CD8+ T-cell population in health and disease.EM CD8+ T cells expressing IL-6R? (IL-6R?(high)) were identified in human peripheral blood and analyzed for function, gene, and transcription factor expression. The relationship of these cells with asthma was determined using blood and sputum.A unique population of IL-6R?(high) EM CD8+ T cells was found in peripheral blood. These cells that potently proliferated, survived, and produced high levels of the Th2-type cytokines IL-5 and IL-13 had increased levels of GATA3 and decreased levels of T-bet and Blimp-1 in comparison with other EM CD8+ T cells. In fact, GATA3 was required for IL-6R? expression. Patients with asthma had an increased frequency of IL-6R?(high) EM CD8+ T cells in peripheral blood compared with healthy control subjects. Also, IL-6R?(high) EM CD8+ T cells exclusively produced IL-5 and IL-13 in response to asthma-associated respiratory syncytial virus and bacterial superantigens.Human IL-6R?(high) EM CD8+ T cells is a unique cell subset that may serve as a reservoir for effector CD8+ T cells, particularly the ones producing Th2-type cytokines, and expand in asthma.
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Project description:The transcription factor IRF4 is required for CD8+ T cell activation, proliferation, and differentiation to effector cells and thus is essential for robust CD8+ T cell responses. The function of IRF4 in memory CD8+ T cells yet needs to be explored. To investigate the role of IRF4 for maintaining differentiation state and survival of CD8+ memory T cells, we used a mouse model with tamoxifen-inducible Irf4 knockout to preclude effects due to inefficient memory cell differentiation in absence of IRF4. We infected mice with ovalbumin-recombinant listeria and induced Irf4 knockout after clearance of the pathogen. Loss of IRF4 resulted in phenotypical changes of CD8+ memory T cells but did not cause a reduction of the total memory T cell population. However, upon reencounter of the pathogen, CD8+ memory T cells showed impaired expansion and acquisition of effector functions. When compared to CD8+ effector memory T cells, CD8+ tissue-resident memory T cells (TRM cells) expressed higher IRF4 levels. Mice with constitutive Irf4 knockout had diminished CD8+ TRM-cell populations, and tamoxifen-induced Irf4 deletion caused a reduction of this cell population. In conclusion, our results demonstrate that IRF4 is required for effective reactivation but not for general survival of CD8+ memory T cells. Formation and maintenance of CD8+ TRM cells, in contrast, appear to depend on IRF4.
| S-EPMC8072204 | biostudies-literature
Project description:Memory phenotype CD4 T cells are found in normal mice and arise through response to environmental antigens or homeostatic mechanisms. The factors that regulate the homeostasis of memory phenotype CD4 cells are not clear. In the present study we demonstrate that there is a marked accumulation of memory phenotype CD4 cells, specifically of the effector memory (T(EM)) phenotype, in lymphoid organs and tissues of mice deficient for the negative co-stimulatory receptor programmed death 1 (PD-1). This can be correlated with decreased apoptosis but not with enhanced homeostatic turnover potential of these cells. PD-1 ablation increased the frequency of memory phenotype CD4 IFN-? producers but decreased the respective frequency of IL-17A-producing cells. In particular, IFN-? producers were more abundant but IL-17A producing cells were more scarce among PD-1 KO T(EM)-phenotype cells relative to WT. Transfer of peripheral naïve CD4 T cells suggested that accumulated PD-1 KO T(EM)-phenotype cells are of peripheral and not of thymic origin. This accumulation effect was mediated by CD4 cell-intrinsic mechanisms as shown by mixed bone marrow chimera experiments. Naïve PD-1 KO CD4 T cells gave rise to higher numbers of TEM-phenotype lymphopenia-induced proliferation memory cells. In conclusion, we provide evidence that PD-1 has an important role in determining the composition and functional aspects of memory phenotype CD4 T cell pool.
| S-EPMC4372408 | biostudies-literature
Project description:Naïve CD4+ T cells were isolated from spleen of AND TcR transgenic/green fluorescence protein (GFP) transgenic mice (Kaye et al., Nature 1989;341:746, Wright et al, Blood 2001;97:2278) that recognize a peptide of pigeon cytochrome C in the context of I-Ek and express CD44lo, CD62Lhi, CD45RBhi, and CD25-. After 4 days in vitro stimulation with antigen presenting cells (APC) under either Th1 or Th2 condition, naïve cells become Th1 or Th2 effector cells expressing CD44hi, CD62L lo, CD45RBhi, and CD25+. Additional 3 days culture in the absence of APC, those effector cells become rested expressing a phenotype similar to memory cells (CD44 hi, CD62L lo, CD45RB lo and CD25-). These rested effector cells were adaptively transferred into thymectomized, lethally irradiated, and T cell depleted bone marrow reconstituted mice and memory cells were isolated after 4-12 weeks by flow sort. Generation and purification of Th1 and Th2 effector and memory CD4+ T cells of 42 samples.
2010-06-10 | E-GEOD-8352 | biostudies-arrayexpress
Project description:Animal models and clinical studies have linked the innate and adaptive immune system to the pathology of Parkinson's disease (PD). Despite such progress, the specific immune responses that influence disease progression have eluded investigators. Herein, we assessed relationships between T cell phenotype and function with PD progression. Peripheral blood lymphocytes from two separate cohorts, a discovery cohort and a validation cohort, totaling 113 PD patients and 96 age- and environment-matched caregivers were examined by flow cytometric analysis and T cell proliferation assays. Increased effector/memory T cells (Tem), defined as CD45RO+ and FAS+ CD4+ T cells and decreased CD31+ and ?4?7+ CD4+ T cells were associated with progressive Unified Parkinson's Disease Rating Scale III scores. However, no associations were seen between immune biomarkers and increased age or disease duration. Impaired abilities of regulatory T cells (Treg) from PD patients to suppress effector T cell function was observed. These data support the concept that chronic immune stimulation, notably Tem activation and Treg dysfunction is linked to PD pathobiology and disease severity, but not disease duration. The association of T cell phenotypes with motor symptoms provides fresh avenues for novel biomarkers and therapeutic designs.
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Project description:The T cell expression of various co-signalling receptors from the CD28 immunoglobulin superfamily (Inducible T cell co-stimulator (ICOS), Programmed cell death 1(PD-1), cytotoxic T lymphocyte associated protein 4 (CTLA-4), B and T lymphocyte attenuator (BTLA) or from the tumour necrosis factor receptor superfamily (glucocorticoid-induced TNFR family related (GITR), 4-1BB, and CD27), is essential for T cell responses regulation. Other receptors (such as T cell immunoglobulin and mucin domain-containing protein 3, T cell immunoglobulin and T cell immunoglobulin and ITIM domain (TIGIT), and lymphocyte activation gene 3) are also involved in this regulation. Disturbance of the balance between activating and inhibitory signals can induce autoimmunity. We have developed an in vitro assay to simultaneously assess the function of naive CD4+ effector T cells (TEFFs), dendritic cells (DCs) and regulatory T cells (TREGs) and the expression of co-signalling receptors. By running the assay on cells from healthy adult, we investigated the regulation of activated T cell proliferation and phenotypes. We observed that TEFFs activated by DCs mainly expressed BTLA, ICOS and PD-1, whereas activated TREGs mainly expressed TIGIT, ICOS, and CD27. Strikingly, we observed that programmed death-ligand 1 (PD-L1) was significantly expressed on both activated TEFFs and TREGs. Moreover, high PD-L1 expression on activated TEFFs was correlated with a higher index of proliferation. Lastly, and in parallel to the TREG-mediated suppression of TEFF proliferation, we observed the specific modulation of the surface expression of PD-L1 (but not other markers) on activated TEFFs. Our results suggest that the regulation of T cell proliferation is correlated with the specific expression of PD-L1 on activated TEFFs.
| S-EPMC8601581 | biostudies-literature
Project description:Constitutive Ras signaling has been shown to augment IL-2 production, reverse anergy, and functionally replace many aspects of CD28 co-stimulation in CD4+ T cells. These data raise the possibility that introduction of active Ras into primary T cells might result in improved functionality in pathologic situations of T cell dysfunction, such as cancer or chronic viral infection. To test the biologic effects of active Ras in primary T cells, CD4+ T cells from Coxsackie-Adenovirus Receptor Transgenic mice were transduced with an adenovirus encoding active Ras. As expected, active Ras augmented IL-2 production in naive CD4+ T cells. However, when cells were cultured for 4 days under conditions to promote effector cell differentiation, active Ras inhibited the ability of CD4+ T cells to acquire a Th1 or Th2 effector cytokine profile. This differentiation defect was not due to deficient STAT4 or STAT6 activation by IL-12 or IL-4, respectively, nor was it associated with deficient induction of T-bet and GATA-3 expression. Impaired effector cytokine production in active Ras-transduced cells was associated with deficient demethylation of the IL-4 gene locus. Our results indicate that, despite augmenting acute activation of naïve T cells, constitutive Ras signaling inhibits the ability of CD4+ T cells to properly differentiate into Th1/Th2 effector cytokine-producing cells, in part by interfering with epigenetic modification of effector gene loci. Alternative strategies to potentiate Ras pathway signaling in T cells in a more regulated fashion should be considered as a therapeutic approach to improve immune responses in vivo.
| S-EPMC4232516 | biostudies-literature
Project description:Murine neonates typically mount Th2-biased immune responses. This entails a cell-intrinsic component whose molecular basis is unknown. We found that neonatal CD4(+) T cells are uniquely poised for rapid Th2 function. Within 24 h of activation, neonatal CD4(+) cells made high levels of IL-4 and IL-13 mRNA and protein. The rapid high-level IL-4 production arose from a small subpopulation of cells, did not require cell cycle entry, and was unaffected by pharmacologic DNA demethylation. CpG methylation analyses in resting neonatal cells revealed pre-existing hypomethylation at a key Th2 cytokine regulatory region, termed conserved noncoding sequence 1 (CNS-1). Robust Th2 function and increased CNS-1 demethylation was a stable property that persisted in neonatal Th2 effectors. The transcription factor STAT6 was not required for CNS-1 demethylation and this state was already established in neonatal CD4 single-positive thymocytes. CNS-1 demethylation levels were much greater in IL-4-expressing CD4 single-positive thymocytes compared with unactivated cells. Together, these results indicate that neonatal CD4+ T cells possess distinct qualities that could predispose them toward rapid, effector-like Th2 function.
| S-EPMC2112939 | biostudies-literature
Project description:Naïve CD4+ T cells were isolated from spleen of AND TcR transgenic/green fluorescence protein (GFP) transgenic mice (Kaye et al., Nature 1989;341:746, Wright et al, Blood 2001;97:2278) that recognize a peptide of pigeon cytochrome C in the context of I-Ek and express CD44lo, CD62Lhi, CD45RBhi, and CD25-. After 4 days in vitro stimulation with antigen presenting cells (APC) under either Th1 or Th2 condition, naïve cells become Th1 or Th2 effector cells expressing CD44hi, CD62L lo, CD45RBhi, and CD25+. Additional 3 days culture in the absence of APC, those effector cells become rested expressing a phenotype similar to memory cells (CD44 hi, CD62L lo, CD45RB lo and CD25-). These rested effector cells were adaptively transferred into thymectomized, lethally irradiated, and T cell depleted bone marrow reconstituted mice and memory cells were isolated after 4-12 weeks by flow sort. Keywords: Microarray analysis of Th1 and Th2 effector and memory CD4+ T cells
2007-07-07 | GSE8352 | GEO